Phase 2 Trial of Deucravacitinib in Psoriatic Arthritis: Biomarkers Associated With Disease Activity, Pharmacodynamics, and Clinical Responses.

OBJECTIVE: Our objective was to evaluate the association of serum biomarkers with baseline psoriatic arthritis (PsA) disease activity, pharmacodynamic effects of deucravacitinib on biomarker levels, and the relationship between biomarkers and clinical responses to deucravacitinib. METHODS: The phase 2 trial (ClinicalTrials.gov identifier: NCT03881059) randomly assigned 203 patients with PsA 1:1:1 to placebo, deucravacitinib at 6 mg once daily (QD), or deucravacitinib at 12 mg QD. Serum biomarkers associated with the interleukin 23 (IL-23) pathway (IL-17A, ß-defensin [BD-2], and IL-19), type I interferon pathway, inflammation, and collagen matrix turnover were measured by immunoassay. Clinical responses (≥75% improvement from baseline in the Psoriasis Area and Severity Index [PASI75] and ≥20% improvement from baseline in American College of Rheumatology criteria [ACR20] responses) were measured at week 16. Hematologic variables were also assessed. RESULTS: IL-17A, BD-2, and IL-19 had a modest association with PASI scores (r = 0.4, r = 0.56, and r = 0.5, respectively) at baseline. In deucravacitinib groups, IL-17A, BD-2, IL-19, C-X-C motif ligand 9 (CXCL9), CXCL10, C-reactive protein, matrix metalloproteinase 3, and collagen type 4 degradation marker levels were significantly reduced at week 16 versus baseline (P < 0.01); higher levels of IL-23 pathway-associated biomarkers predicted higher PASI75 and ACR20 response rates in deucravacitinib-treated patients. Significantly higher PASI75 response rates were seen in patients with high baseline IL-17A (odds ratio 15.76) and BD-2 levels (odds ratio 15.41) versus low baseline IL-17A and BD-2 levels. Changes in hematologic variables that are characteristic of JAK inhibition were not observed with deucravacitinib. CONCLUSION: Deucravacitinib significantly impacted biomarkers associated with Tyk2 signaling pathways of key inflammatory cytokines, including IL-23 and type I interferon, and those related to collagen matrix turnover. These biomarkers may predict treatment responses to deucravacitinib.

Improvements in Patient-Reported Outcomes After Treatment With Deucravacitinib in Patients With Psoriatic Arthritis: Results From a Randomized Phase 2 Trial.

OBJECTIVE: Deucravacitinib, a tyrosine kinase 2 inhibitor, was assessed in a phase 2 trial in patients with active psoriatic arthritis (PsA). Here, we report effects of deucravacitinib from the patient perspective. METHODS: This phase 2, double-blind trial (NCT03881059) randomized patients with active PsA 1:1:1 to deucravacitinib 6 mg once daily (QD), 12 mg QD, or placebo, for 16 weeks. Key secondary end points were changes from baseline (CFBs) at week 16 in Health Assessment Questionnaire-Disability Index (HAQ-DI) and 36-item Short-Form Health Survey (SF-36) physical component summary (PCS) scores. Additional patient-reported outcomes (PROs) assessed disease impact, including fatigue, pain, and mental health. The mean CFBs in PROs and percentages of patients reporting improvements with minimum clinically important differences (MCIDs) or scores of greater than normal values were also assessed. RESULTS: This study comprised 203 patients (51.2% female; mean ± SD age, 49.8 ± 13.5 years). At week 16, the adjusted mean difference (95% confidence interval) versus placebo in HAQ-DI and SF-36 PCS CFB was significant for each deucravacitinib group (HAQ-DI 6 mg, -0.26 [-0.42 to -0.10], P = 0.0020; HAQ-DI 12 mg, -0.28 [-0.45 to -0.12], P = 0.0008; SF-36 PCS 6 mg, 3.3 [0.9 to 5.7], P = 0.0062; SF-36 PCS 12 mg, 3.5 [1.1 to 5.9], P = 0.0042). MCID at week 16 were reported for all PROs with either dose of deucravacitinib. Improvements of MCID or to normative values were reported by more patients receiving deucravacitinib than placebo. CONCLUSION: Deucravacitinib groups demonstrate significant and clinically meaningful improvements in PROs versus placebo in patients with active PsA, which warrants further study.

Evaluation of BMS-986142, a reversible Bruton's tyrosine kinase inhibitor, for the treatment of rheumatoid arthritis: a phase 2, randomised, double-blind, dose-ranging, placebo-controlled, adaptive design study.

BACKGROUND: Bruton's tyrosine kinase (BTK) is a promising biological target for rheumatoid arthritis treatment. This study examined safety, efficacy, and pharmacokinetics of BMS-986142, an oral, reversible BTK inhibitor. The aim was to compare the efficacy of BMS-986142 with placebo on a background of methotrexate in patients with moderate-to-severe rheumatoid arthritis and inadequate response to methotrexate. METHODS: This phase 2, randomised, double-blind, dose-ranging, placebo-controlled, adaptive design study was conducted across 14 countries and 79 clinical sites. We recruited people aged 18 years or older with a documented diagnosis of rheumatoid arthritis at least 16 weeks before screening with an inadequate response to methotrexate with or without inadequate response to up to two tumour necrosis factor inhibitors. Participants were randomly assigned (1:1:1:1) to oral BMS-986142 (100 mg, 200 mg, or 350 mg) or placebo once daily for 12 weeks. Randomisation was done using an interactive voice response system and stratified by prior treatment status and geographical region. All participants, care providers, investigators, and outcome assessors were masked to treatment allocation. Co-primary endpoints were 20% and 70% improvement in American College of Rheumatology criteria (ACR20 and ACR70) at week 12. Primary endpoints were assessed in the efficacy analysis population (all randomised patients who received at least one dose of the study drug and did not discontinue the study). Safety endpoints were analysed in the as-treated analysis population, which included all patients who received at least one dose of the study drug (patients were grouped according to the treatment they actually received vs the treatment to which they were randomised). This trial was registered with ClinicalTrials.gov, number NCT02638948. FINDINGS: Between Feb 24, 2016 and May 3, 2018, 248 patients were randomised (73 in the BMS-986142 100 mg group, 73 in the 200 mg group, 26 in the 350 mg group, and 75 in the placebo group; one post-randomisation exclusion); mean age was 56·7 years (SD 12·7); 214 (87%) of 247 were women, 33 (13%) were men, and 188 (76%) were White. Pre-specified interim analysis resulted in discontinuation of the 350 mg BMS-986142 dose due to elevated liver enzymes and absence of benefit versus placebo. Co-primary endpoints were not met. Response rates for ACR20 (placebo: 23 [31%] of 75; 100 mg: 26 [36%] of 73; 200 mg: 31 [42%] of 73) and ACR70 (placebo: three [4%] of 75; 100 mg: three [4%] of 73; 200 mg: seven [10%] of 73) were not significantly different to placebo; estimate of difference versus placebo for ACR20 was 4·9 (95% CI -10·2 to 20·1; p=0·52) for 100 mg and 11·8 (-3·6 to 27·2; p=0·14) for 200 mg, and for ACR70 the estimate of difference was 0·1 (-16·0 to 16·5; nominal p=1·00) for 100 mg and 5·6 (-10·5 to 21·9; nominal p=0·21) for 200 mg. Six patients experienced serious adverse events (four in the placebo group [mouth ulceration, open globe injury, rheumatoid arthritis flare, and endometrial adenocarcinoma] and two in the BMS-986142 100 mg group [angina pectoris and intestinal obstruction]); there were no deaths. INTERPRETATION: Further investigation of BMS-986142 in people with rheumatoid arthritis is not warranted. An absence of clinical benefit in this study, together with other study results, highlights the need for additional research on the extent of BTK inhibition, treatment duration, and adequacy of drug distribution to inflammation sites, to understand the potential utility of BTK inhibition as a therapeutic strategy for rheumatoid arthritis. FUNDING: Bristol Myers Squibb.

Efficacy and safety of selective TYK2 inhibitor, deucravacitinib, in a phase II trial in psoriatic arthritis.

OBJECTIVE: To evaluate the efficacy and safety of an oral selective tyrosine kinase 2 (TYK2) inhibitor, deucravacitinib, in patients with active psoriatic arthritis (PsA). METHODS: In this double-blind, phase II trial, 203 patients with PsA were randomised 1:1:1 to placebo, deucravacitinib 6 mg once a day or 12 mg once a day. The primary endpoint was American College of Rheumatology-20 (ACR-20) response at week 16. RESULTS: ACR-20 response was significantly higher with deucravacitinib 6 mg once a day (52.9%, p=0.0134) and 12 mg once a day (62.7%, p=0.0004) versus placebo (31.8%) at week 16. Both deucravacitinib doses resulted in significant improvements versus placebo (p≤0.05) in the multiplicity-controlled secondary endpoints of change from baseline in Health Assessment Questionnaire-Disability Index and Short Form-36 Physical Component Summary score and in Psoriasis Area and Severity Index-75 response. Improvements were also seen in multiple exploratory endpoints with deucravacitinib treatment. The most common adverse events (AEs) (≥5%) in deucravacitinib-treated patients were nasopharyngitis, upper respiratory tract infection, sinusitis, bronchitis, rash, headache and diarrhoea. There were no serious AEs and no occurrence of herpes zoster, opportunistic infections and major adverse cardiovascular events, or differences versus placebo in mean changes in laboratory parameters with deucravacitinib treatment. CONCLUSIONS: Treatment with the selective TYK2 inhibitor deucravacitinib was well tolerated and resulted in greater improvements than placebo in ACR-20, multiplicity-controlled secondary endpoints and other exploratory efficacy measures in patients with PsA. Larger trials over longer periods of time with deucravacitinib are warranted to confirm its safety profile and benefits in PsA. TRIAL REGISTRATION NUMBER: NCT03881059.

Patient's experience of psoriatic arthritis: a conceptual model based on qualitative interviews.

INTRODUCTION: Psoriatic arthritis (PsA) is a heterogeneous chronic inflammatory musculoskeletal disorder that manifests as peripheral arthritis, dactylitis, enthesitis and spondylitis. PsA results in significant burden that impacts quality of life of patients. We examined the signs, symptoms and impacts reported by patients with PsA, to characterise the patient experience of PsA and develop a conceptual model representing this patient experience. METHODS: Semi-structured interviews were conducted with patients with PsA recruited through the FORWARD databank. Spontaneous and probed signs, symptoms and impacts of PsA were assessed. Patients rated the disturbance of these concepts on their lives using a scale from 0 ('does not disturb') to 10 ('greatly disturbs'). Signs, symptoms and impacts reported by >80% of patients with a disturbance rating of ≥5 were defined as salient concepts. Recruitment continued until concept saturation was achieved. RESULTS: 19 patients with PsA were interviewed. The interviews elicited 42 symptoms of which 8 had not been identified in a previous literature review encompassing 15 relevant articles. The most salient signs and symptoms elicited in the interviews were joint pain, skin symptoms, stiffness, swollen/inflamed joints and fatigue all with moderate to high disturbance ratings (range: 5.5-7.8). The most salient impacts were sleep disturbance, physical disability, effects on daily activities and feelings of frustration with also moderate to high disturbance ratings (range: 6.1-7.4). CONCLUSIONS: The interviews highlighted the adverse impact PsA has on the patient's life and may inform on outcome variables or areas suitable to be assessed in PsA studies.

Target volume for postoperative radiotherapy in non-small cell lung cancer: results from a prospective trial.

BACKGROUND AND PURPOSE: A previous prospective trial reported that three-dimensional conformal postoperative radiotherapy (PORT) for pN2 NSCLC patients using a limited clinical target volume (CTV) had a late morbidity rate and pulmonary function that did not differ from those observed in pN1 patients treated with surgery without PORT. The aim of this study was to assess locoregional control and localization of failure in patients treated with PORT. MATERIALS AND METHODS: The pattern of locoregional failure was evaluated retrospectively in 151 of 171 patients included in the PORT arm. The CTV included the involved lymph node stations and those with a risk of invasion >10%. Competing risk analysis was used to assess the incidence of locoregional failure and its location outside the CTV. RESULTS: Overall survival at 5years was 27.1% with a median follow-up of 67months for 40 living patients. The 5-year cumulative incidence of locoregional failure was 19.4% (95% CI: 18.2-20.5%) including a failure rate of 2% (95% CI: 0-17%) in locations outside or at the border of the CTV. CONCLUSIONS: The use of limited CTV was associated with acceptable risk of geographic miss. Overall locoregional control was similar to that reported by other studies using PORT for pN2 patients.

Cardiopulmonary morbidity and quality of life in non-small cell lung cancer patients treated with or without postoperative radiotherapy.

AIM: To prospectively assess the cardiopulmonary morbidity and quality of life in patients with non-small cell lung cancer (NSCLC) treated with postoperative radiotherapy (PORT) in comparison to those not receiving PORT. MATERIALS AND METHODS: From 2003 to 2007, 291 patients entered the study; 171 pN2 patients received 3D-planned PORT (PORT group), 120 pN1 patients (non-PORT group) did not. One month after surgery, all patients completed EORTC QLQ C-30 questionnaire and had pulmonary function tests (PFT); cardiopulmonary symptoms were assessed by modified LENT-SOM scale. Two years later, disease-free patients repeated the same examinations. The differences between baseline values and values recorded at two years in QLQ, LENT-SOM and the PFT of the two groups were compared. RESULTS: In the whole cohort, the rate of non-cancer related deaths was 5.3% and 5.0% in PORT and non-PORT group, respectively. Ninety-five patients (47 - PORT group, 48 - non-PORT group) were included into the final analysis. The differences in the QLQ and cardiopulmonary function (LENT/SOM, PFT) between both groups were insignificant. The forced expiratory volume in one second was on average 12.2% and 1.3% better in the PORT and the non-PORT group, respectively, p=0.2. CONCLUSIONS: Our findings support the hypothesis about insignificant morbidity of 3D-planned PORT.

De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases.

OBJECTIVE: Neonatal-onset multisystem inflammatory disease (NOMID; also known as chronic infantile neurologic, cutaneous, articular [CINCA] syndrome) is characterized by fever, chronic meningitis, uveitis, sensorineural hearing loss, urticarial skin rash, and a characteristic deforming arthropathy. We investigated whether patients with this disorder have mutations in CIAS1, the gene which causes Muckle-Wells syndrome and familial cold autoinflammatory syndrome, two dominantly inherited disorders with some similarities to NOMID/CINCA syndrome. METHODS: Genomic DNA from 13 patients with classic manifestations of NOMID/CINCA syndrome and their available parents was screened for CIAS1 mutations by automated DNA sequencing. Cytokine messenger RNA (mRNA) levels were assessed by real-time polymerase chain reaction on peripheral blood leukocyte mRNA, and serum cytokine levels were assayed by enzyme-linked immunosorbent assay. Protein expression was assessed by Western blotting of lysates from plastic-adherent peripheral blood mononuclear cells. RESULTS: In 6 of the 13 patients, we found 6 heterozygous missense substitutions in CIAS1. Five of the 6 mutations are novel. None of these sequence changes was observed in a panel of >900 chromosomes from healthy controls. Two distinct nucleotide changes in a single codon in unrelated patients resulted in the same amino acid change. In 4 mutation-positive children whose parental DNA was available, no mutation was found in the parental DNA, supporting the conclusion that the mutations arose de novo. Consistent with the recently discovered role of CIAS1 in the regulation of interleukin-1 (IL-1), we found evidence of increased IL-1beta, as well as tumor necrosis factor, IL-3, IL-5, and IL-6, but not transforming growth factor beta, in a mutation-positive patient compared with normal controls. CONCLUSION: Our data increase the total number of known germline mutations in CIAS1 to 20, causing a spectrum of diseases ranging from familial cold autoinflammatory syndrome to Muckle-Wells syndrome to NOMID/CINCA syndrome. Mutations in CIAS1 were only found in approximately 50% of the cases identified clinically as NOMID/CINCA syndrome, which raises the possibility of genetic heterogeneity. IL-1 regulation by CIAS1 suggests that IL-1 receptor blockade may constitute a rational approach to the treatment of NOMID/CINCA syndrome.