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Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, inhibits cytokine signaling in psoriasis pathogenesis.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.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).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.The study duration was 1 year.Deucravacitinib demonstrated superiority versus placebo and apremilast and was well tolerated in adults with moderate to severe plaque psoriasis.

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 )

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 )

Effective, well-tolerated oral psoriasis treatments are needed.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.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.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.One-year duration, limited racial diversity.Deucravacitinib was superior to placebo and apremilast across multiple efficacy end points and was well tolerated in moderate to severe plaque psoriasis.

Introduction: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor, is approved by the US Food and Drug Administration for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. In the phase 3 POETYK PSO-1 and PSO-2 trials, deucravacitinib treatment did not result in clinically meaningful changes across multiple laboratory parameters, including liver transaminases and bilirubin. The current analysis assessed changes in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the pooled POETYK PSO-1 and PSO-2 population over 16 weeks. Methods: In POETYK PSO-1 and PSO-2, patients with moderate to severe plaque psoriasis were randomized 1:2:1 to oral placebo, deucravacitinib 6 mg once daily, or apremilast 30 mg twice daily. Patients randomized to placebo crossed over to deucravacitinib at Week 16 in both trials. This analysis uses data from POETYK PSO-1 and PSO-2 pooled by treatment group from Weeks 0-16. ALT and AST were evaluated as mean levels over time, shifts from baseline in Common Terminology Criteria for Adverse Events (CTCAE version 5.0) severity grade, and fold-increase from upper limit of normal (ULN). Patient-level data were evaluated for those who experienced an elevation ≥3´ ULN for ALT or AST in the first 16 weeks of treatment. Results: The pooled POETYK PSO-1 and PSO-2 population included placebo (n=419), deucravacitinib (n=842), and apremilast (n=422). ALT and AST results were available for 413, 833, and 419 patients, respectively. Mean levels of ALT and AST did not change over 16 weeks in any treatment arm. Shifts upwards ≥2 CTCAE grades from baseline in ALT and AST over Weeks 0-16 occurred at a low frequency overall; rates were comparable in patients treated with deucravacitinib (ALT, 0.4%; AST, 0.5%), apremilast (ALT, 0.5%; AST, 0.5%), and placebo (both ALT and AST, 0%). In addition, ALT and AST elevations ≥3´ ULN were infrequent (ALT: placebo 1.2%, deucravacitinib 1.1%, apremilast 0.5%; AST: placebo 0.5%, deucravacitinib 1.6%, apremilast 0.7%). Almost all ALT or AST elevations ≥3´ the ULN between baseline and Week 16 were transient and/or could be traced to underlying liver conditions or concomitant medications. Conclusion: Treatment with deucravacitinib, apremilast, or placebo led to increases in ALT or AST levels from baseline over 16 weeks in a few patients; the increases that did occur were potentially related to underlying liver dysfunction, alcohol use, or use of concomitant medications.

Introduction: Tyrosine kinase 2 (TYK2), an intracellular kinase, mediates signaling of cytokines (IL-23 and Type I interferons) involved in psoriasis pathogenesis. Deucravacitinib, an oral, selective, allosteric TYK2 inhibitor, is approved by the US Food and Drug Administration for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. Deucravacitinib was significantly more efficacious than placebo or apremilast and was well tolerated in the phase 3 POETYK PSO-1 and PSO-2 trials. We evaluated changes in lipid parameters in these trials. Methods: PSO-1 (NCT03624127) and PSO-2 (NCT03611751) were 52-week, double-blind trials conducted globally. Patients with moderate to severe plaque psoriasis (PASI ≥12, sPGA ≥3, BSA involvement ≥10%) were randomized 1:2:1 to oral placebo, deucravacitinib 6 mg once daily, or apremilast 30 mg twice daily. This analysis evaluated serum lipids in patients taking placebo, deucravacitinib, or apremilast during Weeks 0-16 and those taking deucravacitinib continuously during Weeks 0-52 in PSO-1 and PSO-2. Mean changes in total cholesterol, HDL cholesterol, LDL cholesterol, and triglyceride levels are reported, as are shifts from baseline in CTCAE v5 severity grade of hypercholesterolemia and hypertriglyceridemia. Results: 666 and 1020 patients were randomized in PSO-1 and PSO-2, respectively. Mean baseline levels of total cholesterol, HDL cholesterol, and LDL cholesterol were comparable between treatment groups. Mean changes from baseline to Week 16 were small; none was clinically meaningful. Worsening of hypercholesterolemia grade from baseline was observed with similar frequencies among patients receiving placebo, deucravacitinib, and apremilast (10.6%, 11.7%, and 8.4%, respectively); nearly all shifts were 1 grade, and there was no grade ≥3 event. Baseline triglyceride levels were near the upper limit of normal (150 mg/dL) across treatment groups. A 10.3 mg/dL increase in mean triglycerides from baseline to Week 16 was observed with deucravacitinib, but worsening in hypertriglyceridemia >1 grade from baseline was rare (1.2%) and comparable to placebo (1.4%). Most deucravacitinib-treated patients maintained the same or shifted to a lower grade of hypertriglyceridemia from baseline to Week 16. Among patients treated with deucravacitinib continuously for 52 weeks, mean changes in total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides were small. Shifts in >1 grade from baseline for hypercholesterolemia and hypertriglyceridemia were uncommon (0.2% and 1.9%, respectively). No patient discontinued deucravacitinib due to a lipid-related adverse event. Conclusion: There were no meaningful changes in total cholesterol, HDL cholesterol, and LDL cholesterol levels with deucravacitinib treatment. Minimal increases in mean triglyceride levels from baseline to Weeks 16 and 52 were accompanied by very few worsening shifts >1 grade.

Background Optimal treatment for patients with HCV genotype-3 infection and liver cirrhosis remains a medical priority. Daclatasvir+sofosbuvir and ribavirin is a recommended option for such patients, but clinical trial data are lacking for treatment >16 weeks. Methods This was a single-arm, Phase III study of daclatasvir+sofosbuvir+ribavirin for 24 weeks in patients with compensated cirrhosis and HCV genotype-3 infection. The primary end point was sustained virological response at post-treatment week 12 (SVR12); the primary objective was to demonstrate statistical superiority to historical SVR12 data for 12 weeks’ daclatasvir+sofosbuvir without ribavirin in genotype-3-infected patients with cirrhosis (95% CI lower bound >79.0%). Results A total of 78 patients were treated (54 treatment-naive, 24 treatment-experienced including 8 with prior sofosbuvir exposure). SVR12 was achieved by 87% (68/78; 95% CI 77.7, 93.7%) of patients in the primary analysis of central laboratory data. One additional patient achieved SVR12 by local testing resulting in an overall SVR12 rate of 88% (95% CI 79.2, 94.6%) and the lower bound of the 95% CI above the historical threshold. SVR12 rates were 93% (50/54) for treatment-naive and 79% (19/24) for treatment-experienced patients. Of the nine non-SVR12 patients, four were lost to follow-up, two relapsed (both sofosbuvir-experienced), two had end-of-treatment virological failure and one discontinued early. There were no unexpected safety signals; only one patient discontinued for an adverse event. Conclusions Daclatasvir+sofosbuvir+ribavirin for 24 weeks was well tolerated and efficacious in HCV genotype-3-infected patients with compensated cirrhosis, with SVR12 outcomes comparable to previously reported outcomes in patients treated with this regimen for 12–16 weeks.

DCV-TRIO, a fixed-dose combination of daclatasvir (pangenotypic NS5A inhibitor), asunaprevir (NS3/4A protease inhibitor), and beclabuvir (non-nucleoside NS5B inhibitor), has achieved high rates of sustained virologic response at post-treatment Week 12 (SVR12) in phase 3 studies.In this phase 3 study, DCV-TRIO for 12 weeks and daclatasvir plus asunaprevir (DUAL) for 24 weeks were studied in Japanese patients infected with HCV genotype 1 (99 % genotype 1b).SVR12 rates ≥95 % were achieved in both treatment-naive (N = 152) and interferon-experienced (N = 65) cohorts treated with DCV-TRIO for 12 weeks and were comparable across patient subgroups, including patients aged ≥65 years and those with cirrhosis. DUAL recipients (N = 75) had an SVR12 rate of 87 %. In the absence of baseline resistance-associated polymorphisms at positions NS5A-Y93H or -L31, SVR12 rates were 98 % with DCV-TRIO or DUAL. Among genotype 1b-infected patients with baseline Y93H or L31 polymorphisms, 35/38 (92 %) DCV-TRIO recipients, and 7/16 (44 %) DUAL recipients achieved SVR12. Adverse events, mostly liver related, led to treatment discontinuation in 10 % of DCV-TRIO recipients. In this group, SVR12 was achieved by 3/9 patients who discontinued before Week 4 and by 12/12 patients who completed ≥4 weeks of DCV-TRIO. Treatment-related serious adverse events occurred in 4 and 3 % of DCV-TRIO and DUAL recipients, respectively. Seven patients (9 %) discontinued DUAL due to adverse events. No deaths occurred.SVR12 was achieved by 96 % of Japanese patients with HCV genotype 1 infection after 12 weeks of treatment with the DCV-TRIO regimen. DCV-TRIO and DUAL exhibited comparable safety profiles.

Background & aims Daclatasvir has achieved high sustained virologic response (SVR) rates in diverse hepatitis C virus (HCV) populations. This study evaluated the long-term efficacy and safety of daclatasvir-based regimens administered during clinical studies. Methods Patients enrolled within 6 months of parent study completion or protocol availability at the study sites. The primary objective was durability of SVR at follow-up Week 12 (SVR12). Secondary objectives included analyzing HCV sequences in non-responders or responders who relapsed, and characterization of liver disease progression. Results Between 24-February-2012 and 17-July-2015, this study enrolled and began following 1503 recipients of daclatasvir-based regimens (follow-up cut-off, 13-October-2015); 60% were male, 18% aged ≥65 years, 87% had genotype-1a (42%) or -1b (45%) infection, and 18% had cirrhosis. Median follow-up from parent study follow-up Week 12 was 111 (range, 11-246) weeks. 1329/1489 evaluable patients were SVR12 responders; 1316/1329 maintained SVR until their latest visit. Twelve responders relapsed by (n=9) or after (n=3) parent study follow-up Week 24; one was reinfected. Relapse occurred in 3/842 (0.4%) and 9/487 (2%) responders treated with interferon-free or interferon-containing regimens, respectively. Hepatic disease progression and new hepatocellular carcinoma were diagnosed in 15 and 23 patients, respectively. Among non-responders, emergent non-structural protein-5A (NS5A) and -3 (NS3) substitutions were replaced by wild-type sequences in 27/157 (17%) and 35/47 (74%) patients, respectively. Conclusions SVR12 was durable in 99% of recipients of daclatasvir-based regimens. Hepatic disease progression and new hepatocellular carcinoma were infrequent. Emergent NS5A substitutions persisted longer than NS3 substitutions among non-responders. This article is protected by copyright. All rights reserved.

Background & Aims The phase 2, FOURward study (NCT02175966) investigated short-duration therapy (4/6 weeks) with four direct-acting antivirals (DAAs) with distinct mechanisms of action in patients infected with hepatitis C virus (HCV) genotype-1. Methods Non-cirrhotic patients were randomized 1:1 to DCV-TRIO (fixed-dose daclatasvir 30 mg, asunaprevir 200 mg and beclabuvir 75 mg) twice-daily + sofosbuvir 400 mg once-daily for 4 or 6 weeks. The primary endpoint was sustained virological response at post-treatment Week 12 (SVR12). Patients without SVR12 were offered retreatment based on the DAA resistance profile at failure; patients with resistance to ≤1 DCV-TRIO component received DCV-TRIO + RBV for 12 weeks. Results Twenty-eight patients with HCV genotype-1 were enrolled; 79% had genotype-1a infection and median baseline HCV-RNA levels were high (9 × 106 IU/mL). Most patients had undetectable HCV-RNA at end of treatment (96% [n=27/28]); however, relapse occurred in 77% (n=10/13) and 43% (n=6/14) treated for 4 and 6 weeks, leading to SVR12 rates of 29% (n=4/14) and 57% (n=8/14) respectively. SVR12 was higher in patients with lower baseline HCV-RNA (

The aim of this study was to evaluate the effectiveness and overall safety of the Ajust® Adjustable Single-Incision Sling in the treatment of female stress urinary incontinence. This was a prospective, multicenter study conducted in women diagnosed with stress urinary incontinence. The Ajust® Sling was implanted and patients were followed postoperatively for up to 29 months. Evaluations were performed to assess postoperative rate of continence, complications, and patient quality of life (QOL). From November 2008 through May 2009, 52 patients were enrolled and underwent a procedure to implant the Ajust® Sling. Overall, 86.3 % of the patients who successfully received the Ajust® Sling demonstrated total restoration or improvement of continence at the last study visit. QOL scores related to global bladder feeling and lifestyle improved. Only one patient reported the occurrence of mild pain which resolved without treatment or sequelae. In long-term follow-up, the Ajust® Sling was safe and effective, restoring or improving continence in 86.3 % of patients.

Background and Aim Daclatasvir combined with asunaprevir is the first all-oral, ribavirin-free treatment of hepatitis C virus genotype 1b infection in Japan. This study compared the efficacy and safety of daclatasvir plus asunaprevir versus telaprevir plus peginterferon/ribavirin in Japanese treatment-naive patients infected with hepatitis C virus genotype 1b. Methods Treatment-naive patients (20–70 years; baseline viral load, ≥100,000 IU/mL) were randomly assigned (stratified by IL28B rs8099917 TT/non-TT status) to receive either daclatasvir 60 mg tablets once daily and asunaprevir 100 mg softgel capsules twice daily for 24 weeks or telaprevir 750 mg (3 × 250 mg tablets) three times daily for 12 weeks and peginterferon/ribavirin per Japanese prescribing information for 24 weeks. A cohort of prior relapsers to peginterferon/ribavirin (20–75 years; baseline viral load, ≥100,000 IU/mL) received daclatasvir plus asunaprevir. Results In treatment-naive patients, sustained virologic response at post-treatment week 12 in daclatasvir plus asunaprevir recipients was non-inferior (treatment difference, +25.8% in favor of daclatasvir plus asunaprevir) and higher (89.1%, 106/119) than telaprevir plus peginterferon/ribavirin recipients (62.2%, 69/111); sustained viral response was achieved in 95.5% (n = 21/22) of relapsers. Numerically, fewer patients receiving daclatasvir plus asunaprevir compared with telaprevir plus peginterferon/ribavirin experienced serious adverse events (4.2% vs. 5.4%), adverse events leading to discontinuation of any drug (5.0% vs. 62.2%), grade 3/4 treatment-related adverse events (14.3% vs. 72.1%), rash-related events (0% vs. 13.5%), or anemia (0% vs. 47.7%). Conclusion Marked differences were observed in the efficacy and safety profile of daclatasvir in combination with asunaprevir, compared with telaprevir plus peginterferon/ribavirin.

Summary Background An unmet need exists for interferon-free and ribavirin-free treatments for chronic hepatitis C virus (HCV) infection. In this study, we assessed all-oral therapy with daclatasvir (NS5A replication complex inhibitor) plus asunaprevir (NS3 protease inhibitor) in patients with genotype 1b infection, including those with high unmet needs or cirrhosis, or both. Methods We did this phase 3, multicohort study (HALLMARK-DUAL) at 116 sites in 18 countries between May 11, 2012, and Oct 9, 2013. Patients were adults with chronic HCV genotype 1b infection who were treatment-naive; previous non-responders to peginterferon alfa plus ribavirin; or medically ineligible for, previously intolerant of, or ineligible for and intolerant of peginterferon alfa plus ribavirin. Treatment-naive patients were randomly assigned (2:1 ratio) by an interactive voice-response system with a computer-generated random allocation sequence (stratified by cirrhosis status) to receive daclatasvir 60 mg once daily plus asunaprevir 100 mg twice daily or placebo for 12 weeks. Patients and investigator sites were masked to treatment assignment and HCV RNA results to the end of week 12. The treatment-naive group assigned to daclatasvir plus asunaprevir continued open-label treatment to the end of week 24; participants assigned to placebo entered another daclatasvir plus asunaprevir study. Non-responders and ineligible, intolerant, or ineligible and intolerant patients received open-label daclatasvir plus asunaprevir for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12. Efficacy analyses were restricted to patients given daclatasvir plus asunaprevir. This trial is registered with ClinicalTrials.gov, number NCT01581203. Findings This study included 307 treatment-naive patients (205 received daclatasvir plus asunaprevir and 102 received placebo; all randomly assigned patients received the intended treatment), 205 non-responders, and 235 ineligible, intolerant, or ineligible and intolerant patients. Daclatasvir plus asunaprevir provided sustained virological response in 182 (90%, 95% CI 85–94) patients in the treatment-naive cohort, 168 (82%, 77–87) in the non-responder cohort, and 192 (82%, 77–87) in the ineligible, intolerant, or ineligible and intolerant cohort. Serious adverse events occurred in 12 (6%) patients in the treatment-naive group; 11 (5%) non-responders, and 16 (7%) ineligible, intolerant, or ineligible and intolerant patients; adverse events leading to discontinuation (most commonly reversible increases in alanine or aspartate aminotransferase) occurred in six (3%), two (1%), and two (1%) patients, respectively, with no deaths recorded. Grade 3 or 4 laboratory abnormalities were uncommon, with low incidences of aminotransferase increases during the first 12 weeks with daclatasvir plus asunaprevir and placebo in treatment-naive patients (≤2% each). Interpretation Daclatasvir plus asunaprevir provided high sustained virological response rates in treatment-naive, non-responder, and ineligible, intolerant, or ineligible and intolerant patients, and was well tolerated in patients with HCV genotype 1b infection. These results support the use of daclatasvir plus asunaprevir as an all-oral, interferon-free and ribavirin-free treatment option for patients with HCV genotype 1b infection, including those with cirrhosis. Funding Bristol-Myers Squibb.