Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis: Efficacy and safety results from the 52-week, randomized, double-blinded, phase 3 Program fOr Evaluation of TYK2 inhibitor psoriasis second trial.

BACKGROUND: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, inhibits cytokine signaling in psoriasis pathogenesis. OBJECTIVE: The objective of this study was to demonstrate deucravacitinib superiority versus placebo and apremilast in moderate to severe plaque psoriasis based on ≥75% reduction from baseline in Psoriasis Area and Severity Index and a static Physician's Global Assessment score of 0 (clear) or 1 (almost clear) with a ≥2-point improvement from baseline at week 16. METHODS: POETYK psoriasis second trial (NCT03611751), a 52-week, double-blinded, phase 3 trial, randomized patients 2:1:1 to deucravacitinib 6 mg every day (n = 511), placebo (n = 255), or apremilast 30 mg twice a day (n = 254). RESULTS: At week 16, significantly more deucravacitinib-treated patients versus placebo and apremilast patients achieved ≥75% reduction from baseline in Psoriasis Area and Severity Index (53.0% vs 9.4% and 39.8%; P < .0001 vs placebo; P = .0004 vs apremilast) and static Physician's Global Assessment score of 0 or 1 (49.5% vs 8.6% and 33.9%; P < .0001 for both). Efficacy was maintained until week 52 with continuous deucravacitinib. The most frequent adverse event with deucravacitinib was nasopharyngitis. Serious adverse events and discontinuations due to adverse events were infrequent. No clinically meaningful changes were observed in laboratory parameters. LIMITATIONS: The study duration was 1 year. CONCLUSION: Deucravacitinib demonstrated superiority versus placebo and apremilast and was well tolerated in adults with moderate to severe plaque psoriasis.

Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis: Efficacy and safety results from the 52-week, randomized, double-blinded, placebo-controlled phase 3 POETYK PSO-1 trial.

BACKGROUND: Effective, well-tolerated oral psoriasis treatments are needed. OBJECTIVE: To compare the efficacy and safety of deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, versus placebo and apremilast in adults with moderate to severe plaque psoriasis. METHODS: Participants were randomized 2:1:1 to deucravacitinib 6 mg every day (n = 332), placebo (n = 166), or apremilast 30 mg twice a day (n = 168) in the 52-week, double-blinded, phase 3 POETYK PSO-1 trial (NCT03624127). Coprimary end points included response rates for ≥75% reduction from baseline in Psoriasis Area and Severity Index (PASI 75) and static Physician's Global Assessment score of 0 or 1 (sPGA 0/1) with deucravacitinib versus placebo at week 16. RESULTS: At week 16, response rates were significantly higher with deucravacitinib versus placebo or apremilast for PASI 75 (194 [58.4%] vs 21 [12.7%] vs 59 [35.1%]; P < .0001) and sPGA 0/1 (178 [53.6%] vs 12 [7.2%] vs 54 [32.1%]; P < .0001). Efficacy improved beyond week 16 and was maintained through week 52. Adverse event rates with deucravacitinib were similar to those with placebo and apremilast. LIMITATIONS: One-year duration, limited racial diversity. CONCLUSION: Deucravacitinib was superior to placebo and apremilast across multiple efficacy end points and was well tolerated in moderate to severe plaque psoriasis.

Treatment of plaque psoriasis with deucravacitinib (POETYK PSO-1 study): a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a paper published in a medical journal that describes the results of a study called POETYK PSO-1, which looked at a new treatment called deucravacitinib for plaque psoriasis. Plaque psoriasis appears on the body as round or oval raised patches (called plaques) typically covered by scales. This can cause the skin to itch, crack or bleed, and the associated itching and pain can make it difficult to perform basic everyday tasks. Living with psoriasis can cause emotional distress. Treatments are available, but some do not always reduce the symptoms of psoriasis, some may need to be injected or taken multiple times a day, and some may have side effects. Researchers are looking for new treatments that are more effective, convenient to take, and have acceptable safety and tolerability. WHAT HAPPENED IN THE STUDY?: Deucravacitinib is a once-daily pill taken by mouth (orally) that was studied as a treatment for moderate to severe plaque psoriasis in adults in two large studies conducted globally, PSO-1 and PSO-2. The POETYK PSO-1 study compared deucravacitinib with placebo (an inactive pill designed to have no effect) and an approved psoriasis treatment called apremilast, which is a pill taken twice a day. These were tested in adults with moderate to severe plaque psoriasis, which involved 10% or more of their body (equal to 10 or more handprints). The aim of the study was to compare the ability of deucravacitinib with placebo or apremilast to improve psoriasis for the people in the study, and to compare side effects that people had. WHAT DO THE RESULTS OF THE POETYK PSO-1 STUDY SHOW?: After 4 months of treatment, more people taking deucravacitinib had improvements in psoriasis plaques and skin appearance than those taking placebo or apremilast. The study also showed that people continued to see these improvements after taking deucravacitinib for up to 1 year. Side effects are events that happened during the study treatment phase that may or may not be caused by that treatment. Side effects for people taking deucravacitinib were generally mild and occurred in similar numbers overall to those in people taking placebo. The most common side effects in people taking deucravacitinib were inflammation or infection of the nasal (nose) passages and throat. Clinical Trial Registration: NCT03624127 (POETYK PSO-1 study) (ClinicalTrials.gov).

Treatment of plaque psoriasis with deucravacitinib (POETYK PSO-2 study): a plain language summary.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a paper published in a medical journal that describes the results of a study called POETYK PSO-2, which investigated a new treatment for plaque psoriasis. Plaque psoriasis appears on the body as dry, discolored, patches of skin that can be flaky and covered in scales. This can make the skin itch, crack or bleed and make it difficult for people with psoriasis to perform basic everyday tasks. Treatments are available, but some do not always reduce symptoms or may need to be injected or taken multiple times a day, which can be difficult to do, or can have undesirable side effects. Researchers are looking for new treatments for psoriasis. WHAT HAPPENED IN THE STUDY?: Deucravacitinib is a once-daily pill taken by mouth (orally) that was studied as a treatment for moderate to severe plaque psoriasis in two large studies conducted globally, PSO-1 and PSO-2. POETYK PSO-2 was a Phase 3 research study, which is a study that tests a treatment in a large group of participants, that looked at how well deucravacitinib worked in participants with moderate to severe plaque psoriasis compared to a placebo (an inactive pill that has no effect) and an approved psoriasis treatment called apremilast, which is a pill taken twice a day. These medications were tested in adults with moderate to severe plaque psoriasis, which is psoriasis involving 10% or more of their body (equal to 10 or more handprints). The aims of the POETYK PSO-2 study were to find out if treatment with deucravacitinib could improve psoriasis for the participants in the study and to see if there were any side effects. Side effects are events that happened during treatment that may or may not be caused by that treatment. The study also wanted to find out what would happen after stopping treatment with deucravacitinib in participants who had shown major improvements in their psoriasis. WHAT DO THE RESULTS OF THE POETYK PSO-2 STUDY SHOW?: After 4 months of treatment, more participants taking deucravacitinib had significantly greater improvements in psoriasis than those taking placebo or apremilast. The study also showed that participants continued to see these improvements after taking deucravacitinib for up to 1 year. Some participants maintained the improvements in their psoriasis with deucravacitinib after stopping treatment and switching to a placebo. Side effects for participants taking deucravacitinib were generally mild and occurred in similar numbers to those in participants taking placebo. The most common side effects in participants taking deucravacitinib were inflammation of the nose and throat (a common cold) which occurred at a similar rate in participants who took placebo. Clinical Trial Registration: NCT03611751 (POETYK PSO-2 study) (ClinicalTrials.gov).

Lack of Electrocardiographic Effects of Deucravacitinib in Healthy Subjects.

Deucravacitinib is a novel, oral, selective inhibitor of the intracellular signaling kinase tyrosine kinase 2. This phase 1, randomized, partially double-blind, 4-period crossover study in healthy adults was conducted to determine whether deucravacitinib 12 mg (therapeutic dose) or 36 mg (supratherapeutic dose) had a clinically relevant effect on the corrected QT interval and other electrocardiographic (ECG) parameters. Subjects received 1 of 4 sequences of placebo, deucravacitinib 12 mg, deucravacitinib 36 mg, and moxifloxacin 400 mg (positive control) in a randomized crossover fashion. The placebo-corrected change from baseline for the QT interval corrected for heart rate using the Fridericia method (QTcF), ECG parameters, and safety measures were evaluated. A clinically meaningful QTcF prolongation of >10 milliseconds was not found for deucravacitinib at tested doses. Assay sensitivity was demonstrated by the observation of known QT effects of moxifloxacin in the study. Deucravacitinib had no clinically relevant effect on other parameters and was generally well tolerated. The majority of adverse events (AEs) were mild, and all AEs resolved by study's end. Three treatment-related serious AEs of pharyngitis, cellulitis, and lymphadenopathy occurred in 1 subject following administration of deucravacitinib 12 mg, but resolved by end of study. This study demonstrated that a single oral dose of deucravacitinib 12 or 36 mg did not produce a clinically relevant effect on the corrected QT interval or other measured ECG parameters in healthy adults.

Selectivity Profile of the Tyrosine Kinase 2 Inhibitor Deucravacitinib Compared with Janus Kinase 1/2/3 Inhibitors.

INTRODUCTION: Deucravacitinib, a novel, oral, selective inhibitor of tyrosine kinase 2 (TYK2) signaling, acts via an allosteric mechanism by binding to the enzyme's regulatory domain instead of the catalytic domain. This unique binding provides high functional selectivity for TYK2 versus the closely related Janus kinases (JAKs) 1/2/3. Deucravacitinib was efficacious in phase 2 and 3 psoriasis trials, without clinical or laboratory parameters indicative of JAK 1/2/3 inhibition being observed. This analysis compared the kinase specificities of deucravacitinib versus JAK 1/2/3 inhibitors at therapeutic exposures. METHODS: Signaling via JAK 1/3, JAK 2/2, and TYK2/JAK 2 dimers was measured in in vitro whole blood assays. Concentrations providing half-maximal inhibition (IC50) in these assays were determined for deucravacitinib and the JAK 1/2/3 inhibitors tofacitinib, upadacitinib, and baricitinib. Newly derived whole blood IC50 values were plotted against available pharmacokinetic profiles using doses evaluated in phase 2/3 trials. Simulated average daily inhibition and durations over which concentrations exceeded IC50 were evaluated. RESULTS: At clinically relevant exposures, projected steady-state deucravacitinib plasma concentrations were higher than TYK2 IC50 for approximately 9-18 h. Maximal plasma concentrations (Cmax) of deucravacitinib were 8- to 17-fold lower than JAK 1/3 IC50 and > 48- to > 102-fold lower than JAK 2/2 IC50. Simulated daily average TYK2 inhibition by deucravacitinib ranged from 50% to 69%. Simulations indicated that tofacitinib, upadacitinib, and baricitinib at steady state exhibited varying degrees of JAK 1/3 (daily average inhibition, 70-94%) and JAK 2/2 (23%-67%) inhibition at therapeutic concentrations, with Cmax values 17- to 33-fold lower than their TYK2 IC50 levels. CONCLUSION: At clinically relevant doses and exposures, deucravacitinib demonstrates highly selective inhibition of TYK2 and not JAK 1/2/3. Tofacitinib, upadacitinib, and baricitinib variably inhibit JAK 1/2/3 but not TYK2. These results indicate that deucravacitinib is a distinct class of kinase inhibitor compared with JAK 1/2/3 inhibitors.

Psoriasis is a common, chronic inflammatory skin condition that impairs patients' physical health, emotional well-being, work performance, and overall quality of life. Psoriasis and related conditions such as psoriatic arthritis are caused by abnormalities in the immune system. Various drugs are used or explored to treat these conditions, including Janus kinase (JAK) inhibitors; however, JAK inhibitors are associated with a range of side effects such as abnormal changes in blood cell, cholesterol, and triglyceride levels, as well as liver and kidney dysfunction. Deucravacitinib is a new oral drug in development that blocks a key molecule involved in the pathogenesis of psoriasis known as tyrosine kinase 2 (TYK2). This analysis compared the selectivity of deucravacitinib versus approved JAK 1/2/3 inhibitors (tofacitinib, upadacitinib, and baricitinib) for TYK2 and JAK 1/2/3 in whole blood assays, using therapeutic doses of each drug. The authors reported that deucravacitinib inhibits TYK2 with minimal or no inhibition of JAK 1/2/3. In contrast, tofacitinib, upadacitinib, and baricitinib inhibit JAK 1, JAK 2, and/or JAK 3 to various degrees but do not inhibit TYK2. These results demonstrate that deucravacitinib is a distinct class of drug compared with the JAK 1/2/3 inhibitors. The results of this analysis are consistent with those of two recently completed phase 3 trials in patients with moderate-to-severe plaque psoriasis (POETYK PSO-1 and PSO-2), as well as a phase 2 trial in psoriasis, in which deucravacitinib was efficacious and well tolerated, without clinical or laboratory abnormalities suggestive of JAK 1/2/3 inhibition being observed.

Population Pharmacokinetic Analysis of BMS-986166, a Novel Selective Sphingosine-1-Phosphate-1 Receptor Modulator, and Exposure-Response Assessment of Lymphocyte Counts and Heart Rate in Healthy Participants.

Sphingosine-1-phosphate (S1P) binding to the S1P-1 receptor (S1P1R) controls the egress of lymphocytes from lymphoid organs and targets modulation of immune responses in autoimmune diseases. Pharmacologic modulation of S1P receptors has been linked to heart rate reduction. BMS-986166, a prodrug of the active phosphorylated metabolite BMS-986166-P, presents an improved cardiac safety profile in preclinical studies compared to other S1P1R modulators. The pharmacokinetics, safety, and pharmacodynamics of BMS-986166 versus placebo after single (0.75-5.0 mg) and repeated (0.25-1.5 mg/day) oral administration were assessed in healthy participants after a 1-day lead-in placebo period. A population model was developed to jointly describe BMS-986166 and BMS-986166-P pharmacokinetics and predict individual exposures. Inhibitory sigmoid models described the relationships between average daily BMS-986166-P concentrations and nadir of time-matched (day -1) placebo-corrected heart rate on day 1 (nDDHR, where DD represents ∆∆) and nadir of absolute lymphocyte count (nALC). Predicted decreases in nDDHR and nALC were 9 bpm and 20% following placebo, with maximum decreases of 10 bpm in nDDHR due to drug effect, and approximately 80% in nALC due to drug and placebo. A 0.5-mg/day dose regimen achieves the target 65% reduction in nALC associated with a 2-bpm decrease in nDDHR over placebo.

The safety and pharmacokinetics of a novel, selective S1P1R modulator in healthy participants.

Background: Safety, pharmacokinetics and pharmacodynamics of BMS-986166, a novel sphingosine-1-phosphate receptor 1 modulator, were assessed.Research design and methods: Two double-blind, placebo-controlled, randomized Phase l studies were conducted in healthy participants. In the single ascending dose study (N = 70), BMS-986166 was administered as a single dose, upwardly titrated daily doses or a single dose in participants who were fed, fasted or administered famotidine. In the multiple ascending dose study (N = 32), BMS-986166 was administered daily for 28 days. Safety, pharmacokinetics and pharmacodynamics (absolute lymphocyte count [ALC]) were assessed.Results: BMS-986166 was generally well tolerated; treatment-related adverse events were mild. Dose-related, clinically insignificant reductions in time-matched heart rate were recorded versus placebo. Pharmacokinetics were linear and stationary with approximately dose-related increases in blood exposure of BMS-986166. Decreases in ALC percent change from baseline with multiple doses of BMS-986166 versus placebo were dose-related. Between Day 0 and 35, median nadir lymphocyte reductions were 53.7%, 75.9% and 81.9% with 0.25-, 0.75- and 1.5-mg BMS-986166 doses. ALC recovery began 14, 14-21 and 7 days after last dose of 0.25, 0.75 and 1.5 mg.Conclusions: BMS-986166 was generally well tolerated in this population and warrants further investigation.Trial registration: ClinicalTrials.gov: NCT02790125, NCT03038711.

Modeling and Simulation of the Pharmacokinetics and Target Engagement of an Antagonist Monoclonal Antibody to Interferon-γ-Induced Protein 10, BMS-986184, in Healthy Participants to Guide Therapeutic Dosing.

BMS-986184 is a human, second-generation, anti-interferon-γ-induced protein 10 (IP-10) monoclonal antibody. In this study the pharmacokinetics and target engagement (TE) of BMS-986184 in healthy participants were characterized using population-based target-mediated drug disposition (TMDD) modeling and data from a first-in-human study (NCT02864264). The results of the first-in-human study and the model generated were used to conduct stochastic simulations of a virtual population of healthy participants to predict pharmacokinetic exposures and TE responses for different dosage regimens. A 2-compartment, 2-target, TMDD structural model, assuming quasi-steady-state and stimulated production on treatment, was developed by simultaneous fitting of the total drug, serum-free IP-10, and serum total IP-10 concentration data, with the second unobservable target contribution to drug elimination described by the Michaelis-Menten elimination term. Model evaluation confirmed agreement between model predictions and observed data. Simulation of a virtual population of healthy individuals demonstrated that steady state was reached at the eighth dosing interval, and that around 150 mg subcutaneously every other week could be a suitable target dosage regimen for future clinical trials. Integrated modeling strategies such as this can be used to help guide rational clinical trial development of drugs with TMDD, leading to improved dose selection and greater patient benefits.

Effects of Urotensin II Receptor Antagonist, GSK1440115, in Asthma.

BACKGROUND: Urotensin II (U-II) is highly expressed in the human lung and has been implicated in regulating respiratory physiology in preclinical studies. Our objective was to test antagonism of the urotensin (UT) receptor by GSK1440115, a novel, competitive, and selective inhibitor of the UT receptor, as a therapeutic strategy for the treatment of asthma. METHODS: Safety, tolerability, and pharmacokinetics (PK) of single doses of GSK1440115 (1-750 mg) were assessed in a Phase I, placebo controlled study in 70 healthy subjects. In a Phase Ib study, 12 asthmatic patients were randomized into a two-period, single-blind crossover study and treated with single doses of 750 mg GSK1440115 or placebo and given a methacholine challenge. RESULTS: Administration of GSK1440115 was safe and well-tolerated in healthy subjects and asthmatic patients. In both studies, there was a high degree of variability in the observed PK following oral dosing with GSK1440115 at all doses. There was a marked food effect in healthy subjects at the 50 mg dose. In the presence of food at the 750 mg dose, the time to maximal concentration was between 2 and 6 h and the terminal half-life was short at approximately 2 h. All asthmatic patients maintained greater than the predicted concentration levels necessary to achieve predicted 96% receptor occupancy for ≥3 h (between 4 and 7 h post-dose). There were no apparent trends or relationships between the systemic plasma exposure of GSK1440115 and pharmacodynamic endpoints, PC20 after methacholine challenge and FEV1, in asthmatics. CONCLUSION: While GSK1440115 was safe and well-tolerated, it did not induce bronchodilation in asthmatics, or protect against methacholine-induced bronchospasm, suggesting that acute UT antagonism is not likely to provide benefit as an acute bronchodilator in this patient population.

Biochemical characterization of the first essential two-component signal transduction system from Staphylococcus aureus and Streptococcus pneumoniae.

The YYCFG two-component signal transduction system (TCSTS) has been shown to be essential to the viability of several gram-positive bacteria. However, the function of the gene pair remains unknown. Interestingly, while both components are essential to Staphylococcus aureus and Bacillus subtilis, only the response regulator (YYCF) is essential to Streptococcus pneumoniae. To study this essential TCSTS further, the S. pneumoniae and S. aureus truncated YycG histidine kinase and full-length YycF response regulator proteins were characterized at a biochemical level. The recombinant proteins from both organisms were expressed in Escherichia coli and purified. The YycG autophosphorylation activities were activated by ammonium. The apparent K(m )(ATP) of S. aureus YycG autophosphorylation was 130 microM and S. pneumoniae was 3.0 microM. Each had similar K(cat )values of 0.036 and 0.024 min(-1), respectively. Cognate phosphotransfer was also investigated indicating different levels of the phosphorylated YycG intermediates during the reaction. The S. pneumoniae YycG phosphorylated intermediate was not detectable in the presence of its cognate YycF, while phosphorylated S. aureus YycG and YycF were detected concurrently. In addition, noncognate phosphotransfer was demonstrated between the two species. These studies thoroughly compare the essential YycFG TCSTS from the two species at the biochemical level and also establish methods for assaying the activities of these antibacterial targets.