Johnson & Johnson (Canada)

Varying hair textures and hair care practices contribute to nuances in clinical presentation and management of scalp psoriasis across diverse patient populations. Cohort B of the VISIBLE trial enrolled participants with moderate to severe scalp psoriasis and skin of color, across the skin-tone spectrum. To evaluate efficacy, quality of life, and adverse event outcomes of guselkumab, 100 mg, among participants with moderate to severe scalp psoriasis and skin of color over 48 weeks. This ongoing phase 3b, randomized clinical trial at 45 sites in the US and Canada enrolled adults with skin of color and moderate to severe scalp psoriasis (scalp surface area [SSA] ≥30%; Psoriasis Scalp Severity Index [PSSI] ≥12; scalp-specific Investigator's Global Assessment [ss-IGA] score ≥3; ≥1 nonscalp plaque). Data were collected from September 2022 to June 2024. Randomized participants (3:1) received guselkumab, 100 mg, at weeks 0, 4, and every 8 weeks, or placebo at weeks 0, 4, and 12, then guselkumab at weeks 16, 20, and every 8 weeks. Coprimary end points were ss-IGA score of 0 or 1 (ss-IGA 0/1) and 90% or greater improvement in PSSI (PSSI 90) at week 16 (guselkumab vs placebo). Major secondary end points included ss-IGA 0 (complete scalp clearance), PSSI 100, percentage changes from baseline in PSSI and SSA, changes from baseline in Dermatology Life Quality Index (DLQI) and Psoriasis Symptoms and Signs Diary (PSSD) symptoms score, and 4-point or greater reduction in Scalp Itch Numeric Rating Scale (NRS) score. Of 108 participants (81 randomized to guselkumab; 27 randomized to placebo), 100 (92.6%) completed 48 weeks of treatment. The mean (SD) age overall was 42.5 (13.6) years, and 58 participants (56.9%) were male. At the week 16 primary end point, in the guselkumab (n = 76) vs placebo (n = 26) groups, respectively, response rates were as follows: ss-IGA 0/1, 68.4% (n = 52) vs 11.5% (n = 3) (P < .001); PSSI 90, 65.8% (n = 50) vs 3.8% (n = 1) (P < .001); ss-IGA 0, 57.9% (n = 44) vs 3.8% (n = 1) (P < .001); PSSI 100, 59.2% (n = 45) vs 3.8% (n = 1) (P < .001); 4-point or greater reduction in Scalp Itch NRS score (in those with a baseline score of at least 4), 69.4% (n = 50 of 72) vs 24.0% (n = 6 of 25) (P < .001). Guselkumab efficacy increased and was maintained through week 48, when guselkumab-randomized participants achieved mean (SD) percentage improvements in PSSI and SSA of 94.6% (12.2%) and 94.8% (16.2%), respectively, and 51 (67.1%) achieved ss-IGA 0. DLQI and PSSD symptoms score least-squares mean changes were -9.7 (95% CI, -11.1 to -8.2) vs -2.2 (95% CI, -4.8 to 0.4) (P < .001) and -44.8 (95% CI, -50.6 to -39.1) vs -8.3 (95% CI, -18.4 to 1.9) (P < .001), respectively, with sustained improvements through week 48. Through week 16, infections were the most common adverse events in the guselkumab (n = 12; 14.8%) and placebo (n = 1; 3.7%) groups. In this randomized clinical trial, after 3 doses of guselkumab, most participants achieved significant scalp clearance and clinically meaningful quality-of-life improvements; improvements increased and were maintained through week 48. ClinicalTrials.gov Identifier: NCT05272150.

5017 Background: Human kallikrein 2 (encoded by the KLK2 gene and hereafter referred to as KLK2) is a novel target expressed on PC cells with limited normal tissue expression. Pasritamig is a first-in-class T-cell-redirecting bispecific antibody that simultaneously binds KLK2 on PC cells and CD3 receptor complexes on T cells. We report dose escalation and expansion results from a first-in-human study (NCT04898634) evaluating pasritamig in pts with mCRPC. Methods: Pasritamig target doses (TDs) were escalated from 0.5-2000 mg SC and 150-900 mg IV QW-Q6W, with various step-up (SU) dosing schedules. Pre-medication with dexamethasone (16 mg) was required in SU and 1 st TD. The primary objective was to determine the safety and RP2D. Secondary objectives included preliminary assessment of antitumor activity. Results: As of October 7, 2024, 174 pts (median [range] age 69 [36-89] years) had received ≥1 pasritamig dose (Table). Pts had a median of 4 prior therapies (range 1-13; 99.4% ARPI, 78.2% taxane chemotherapy, 17.2% lutetium Lu 177 vipivotide tetraxetan). There were no pasritamig-related deaths. One pt experienced a DLT of transient Gr 3 ALT/AST elevation after 50 mg SU2 SC administration. While most pts reported ≥1 TRAE (82.2% overall; 68.1% IV; 92.2% SC), these were mostly low grade, with only 9.2% of pts (6.9% IV; 10.8% SC) experiencing a Gr ≥3 TRAE. In the RP2D safety population (n=45; 3.5 mg [Day 1], 18 mg [Day 8], 300 mg Q3W or Q6W IV), the most common TRAEs were infusion-related reactions (22.2%; Gr 1/2), fatigue (15.6%; Gr 1/2), and CRS (8.9%; all Gr 1, no tocilizumab was administered), no TRAEs led to treatment discontinuation, no ICANS was observed, and 2 serious TRAEs (Gr 1 CRS) were reported. In the RP2D efficacy population (n=33; 3.5 mg [Day 1], 18 mg [Day 8], 300 mg Q6W IV), PSA50 was 42.4% (14/33) and median rPFS was 6.77 (95% CI 2.89, NE) months with 39.4% of pts ongoing (13/33). ORR in the 85 pts with measurable disease was 16.1% (n=5/31) in pts with lymph node +/- bone and 3.7% (n=2/54) in pts with visceral disease, with a median DOR of 11.27 (95% CI 3.58, NE) months. Conclusions: Pasritamig was very well tolerated (&lt;10% of pts experienced CRS [all Gr1] at the RP2D) with promising antitumor activity, demonstrating proof of concept for KLK2 as a target amenable to T-cell redirection. These results address an unmet need for a targeted T-cell based therapy that is safe to administer in an outpatient setting with clinically meaningful benefit in mCRPC. Phase 3 trials are planned. Clinical trial information: NCT04898634 . TotalN=174 SCn=102 IVn=72 RP2Dn=45 a TRAEs leading to treatment discontinuation, n (%) 1 (0.6) 1 (1.0) 0 0 Gr ≥3 TRAEs, n (%) 16 (9.2) 11 (10.8) 5 (6.9) 2 (4.4) CRS, n (%) 43 (24.7) 31 (30.4) 12 (16.7) 4 (8.9) Gr 1 37 (21.3) 28 (27.5) 9 (12.5) 4 (8.9) Gr 2 6 (3.4) 3 (2.9) 3 (4.2) 0 Radiographic PFS, months, median (95% CI) 4.40 (3.35, 6.47) 4.07 (2.79, 4.93) 5.88 (3.15, NE) 6.77 (2.89, NE) b a RP2D safety pop.=TD 300 mg Q3W/Q6W. b RP2D efficacy pop.=TD 300 mg Q6W (n=33).

Background: Although it is generally believed that infliximab dose optimization in patients with inflammatory bowel disease with low serum infliximab concentration at trough results in increased treatment persistence, empirical data to support this notion are lacking. This study evaluated the association of infliximab therapeutic drug monitoring (TDM) and TDM-associated dose optimization with persistence in real-world practice. Methods: Data from adults with Crohn's disease (CD) or ulcerative colitis (UC) who participated in a national patient support program (PSP) in Canada were analyzed. Participants who had a first TDM evaluation (with a recorded infliximab trough concentration) in the maintenance phase of treatment were assessed (excluding those who underwent prior dose optimization). Persistence was evaluated using time-dependent Cox proportional hazards models. Results: In the overall population of patients with CD or UC, TDM was not associated with longer persistence (n = 13,203). In patients with no prior dose optimization (n = 2729) who had a serum infliximab concentration of < 3 μg/mL, dose optimization within 9 weeks of TDM was associated with significantly longer persistence (HR: 0.36; 95% CI: 0.26, 0.50 for CD [n = 711] and HR: 0.30, 95% CI: 0.21, 0.43 for UC [n = 501]). Sensitivity analyses yielded similar results when using a threshold concentration of < 5 μg/mL. In an analysis excluding patients who received no further treatment after TDM, the association between dose optimization and longer persistence was not confirmed in patients with CD, and mostly confirmed in patients with UC at a threshold concentration of < 3 μg/mL. Conclusion: TDM-associated dose optimization in patients with UC with low serum infliximab concentrations was associated with longer persistence. This association was not confirmed in patients with CD. This study demonstrated that real-world data from a PSP-generated cohort can be evaluated to inform clinical practice and that this approach may be complementary to other types of cohort studies.

We evaluated longitudinal rates, risk factors, and costs of superficial and deep incisional surgical-site infection (SSI) 6 months after primary total knee arthroplasty (pTKA) and revision total knee arthroplasty (rTKA). Patients were identified from January 1, 2016 through March 31, 2018, in the IBM MarketScan administrative claims databases. Kaplan-Meier survival curves evaluated time to SSI over 6 months. Cox proportional hazard models evaluated SSI risk factors. Generalized linear models estimated SSI costs up to 12 months. Of the 26,097 pTKA patients analyzed (mean age, 61.6 years; SD, 9.2; 61.4% female; 60.4% commercial insurance), 0.65% (95% CI, 0.56%-0.75%) presented with a deep incisional SSI and 0.82% (95% CI, 0.71%-0.93%) with a superficial incisional SSI. Also, 3,663 patients who had rTKA (mean age, 60.9 years; SD, 10.1; 60.6% female; 53.0% commercial insurance), 10.44% (95% CI, 9.36%-11.51%) presented with a deep incisional SSI and 2.60% (95% CI, 2.07%-3.13%) presented with a superficial incisional SSI. Infections were associated with male sex and multiple patient comorbidities including chronic pulmonary disease, pulmonary circulatory disorders, fluid and electrolyte disorders, malnutrition, drug abuse, and depression. Adjusted average all-cause incremental commercial cost ranged from $14,298 to $29,176 and from $41,381 to 59,491 for superficial and deep incisional SSI, respectively. SSI occurred most frequently following rTKA and among patients with pulmonary comorbidities and depression. The incremental costs associated with SSI following TKA were substantial.

Background and AimsDespite recent approvals for new drugs to treat adults with Crohn’s disease or ulcerative colitis, there are only two approved advanced treatment options [infliximab and adalimumab] for children with inflammatory bowel disease [IBD]. There are many potential new therapies being developed for adult and paediatric IBD. Moreover, regulatory agencies in both the European Union and USA have processes in place to support the early planning and initiation of paediatric studies. Nevertheless, unacceptable delays in approvals for use of drugs in children persist, with an average 7-year gap, or longer, between authorization of new IBD drugs for adults and children.MethodsA 2-day virtual meeting was held during April 14–15, 2021 for multi-stakeholders [clinical academics, patient community, pharmaceutical companies and regulators] to discuss their perspectives on paediatric drug development for IBD.ResultsThe multi-stakeholder group presented, discussed and proposed actions to achieve expediting the approval of new drugs in development for paediatric IBD.ConclusionsCollaborative action points for all stakeholders are required to make progress and facilitate new drug development for children with IBD.

Objective We conducted literature reviews to uncover differential effects of sex on sequelae from coronavirus disease 2019 (COVID-19) and on long COVID syndrome. Methods Two authors independently searched OvidSP in Embase, Medline, Biosis, and Derwent Drug File. Publications reporting original, sex-disaggregated data for sequelae of COVID-19 (published before August 2020) and long COVID syndrome (published before June 2021) were included in the reviews. The association between COVID-19 sequelae (i.e. lasting <4 weeks after symptom onset) and sex, and between long COVID syndrome (i.e. lasting >4 weeks after symptom onset) and sex, was determined by odds ratio (OR) and 95% confidence interval (CI) (statistical significance defined by 95% CI not including 1). Results Of 4346 publications identified, 23 and 12 met eligibility criteria for COVID-19 sequelae and long COVID syndrome, respectively. COVID-19 sequelae in the categories of psychiatric/mood (OR = 1.80; 95% CI: 1.35–2.41), ENT (OR = 1.42; 95% CI: 1.39–1.46), musculoskeletal (OR = 1.15; 95% CI: 1.14–1.16), and respiratory (OR = 1.09; 95% CI: 1.08–1.11) were significantly more likely among females (vs. males), whereas renal sequelae (OR = 0.83; 95% CI: 0.75–0.93) were significantly more likely among males. The likelihood of having long COVID syndrome was significantly greater among females (OR = 1.22; 95% CI: 1.13–1.32), with the odds of ENT (OR = 2.28; 95% CI: 1.94–2.67), GI (OR = 1.60; 95% CI: 1.04–2.44), psychiatric/mood (OR = 1.58; 95% CI: 1.37–1.82), neurological (OR = 1.30; 95% CI: 1.03–1.63), dermatological (OR = 1.29; 95% CI: 1.05–1.58), and other (OR = 1.36; 95% CI: 1.25–1.49) disorders significantly higher among females and the odds of endocrine (OR = 0.75; 95% CI: 0.69–0.81) and renal disorders (OR = 0.74; 95% CI: 0.64–0.86) significantly higher among males. Conclusions Sex-disaggregated differences for COVID-19 sequelae and long COVID syndrome were observed. Few COVID-19 studies report sex-disaggregated data, underscoring the need for further sex-based research/reporting of COVID-19 disease.

The design, synthesis and antibacterial activity of novel glycopeptide/beta-lactam heterodimers is reported. Employing a multivalent approach to drug discovery, vancomycin and cephalosporin synthons, A and B respectively, were chemically linked to yield heterodimer antibiotics. These novel compounds were designed to inhibit Gram-positive bacterial cell wall biosynthesis by simultaneously targeting the principal cellular targets of both glycopeptides and beta-lactams. The antibiotics 8a-f displayed remarkable potency against a wide range of Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA). Compound 8e demonstrated excellent bactericidal activity against MRSA (ATCC 33591) and initial evidence supports a multivalent mechanism of action for this important new class of antibiotic.