Concomitant Corticosteroid Research Articles

Dupilumab Efficacy in Children With Atopic Dermatitis Aged 6 Months to 5 Years With and Without Atopic Comorbidities

Atopic dermatitis (AD) is a chronic inflammatory systemic disease that frequently occurs with atopic comorbidities. Here, we evaluate the efficacy of dupilumab with concomitant topical corticosteroids (TCS) for moderate-to-severe AD in children with and without asthma, allergic rhinitis, and food allergies.

P719 Symptomatic improvement and long-term stability of ulcerative colitis symptoms over 3 years of ozanimod treatment

Abstract Background The phase 3 True North (TN) study demonstrated the efficacy and safety of ozanimod over 52 weeks in patients (pts) with moderately to severely active ulcerative colitis (UC). Pts completing 52 weeks of TN were eligible for the ongoing TN open-label extension (OLE) assessing the long-term efficacy and safety of ozanimod. Presented here is the interim analysis of the TN OLE focused on the symptomatic efficacy of ozanimod in pts with approximately 3 years of continuous ozanimod treatment. Methods Pts who achieved clinical response after receiving 52 weeks of continuous ozanimod during TN and subsequently entered the TN OLE were evaluated (data cutoff: 10 January 2022, at which point the OLE Week 94 disposition was available for pts). Patient-reported (rectal bleeding subscore [RBS] and stool frequency subscore [SFS]) and clinician-reported (Physician’s Global Assessment) symptomatic outcomes were determined. Symptomatic clinical response (partial Mayo score [PMS] ≥1 point and ≥30% reduction in PMS with ≥1-point decrease in RBS or absolute RBS of ≤1) and symptomatic clinical remission (RBS=0 and SFS ≤1 [and decrease of ≥1 point from baseline SFS]) were evaluated at OLE Week 5 through OLE Week 94 (146 weeks of continuous ozanimod treatment) using observed case (OC) and nonresponder imputation (NRI) analyses. PMS, RBS, and SFS were assessed from TN baseline to OLE Week 94. Results In all, 131 pts entered the OLE after achieving clinical response following 52 weeks of continuous ozanimod during TN. At data cutoff, 87.0% completed OLE Week 46 (98 weeks of continuous ozanimod) and 71.8% completed OLE Week 94 (146 weeks of continuous ozanimod). Pts had a mean age of 44 years and 52% were female. Most (68%) had left-sided UC disease, 24% had concomitant corticosteroid use at TN baseline, and 32% had prior exposure to tumor necrosis factor inhibitors. Symptomatic clinical response and symptomatic clinical remission were observed in 100.0% (Figure 1A) and 84.4% (Figure 2A) of pts, respectively, at OLE Week 5 in the OC analysis (93.1% [Figure 1B] and 78.6% [Figure 2B] in the NRI analysis). Rates of symptomatic clinical response and symptomatic clinical remission were maintained through OLE Week 94 in the OC analysis and decreased slightly over time in the NRI analysis. Reductions in mean PMS from baseline were observed during TN and sustained through OLE Week 94. Reductions from TN baseline in RBS (Figure 3) and SFS (Figure 4) were also observed through OLE Week 94. Conclusion This interim analysis of the TN OLE focusing on symptomatic endpoints found that most pts who achieved clinical response after 1 year of ozanimod sustained symptom control for another 2 years.

DOP37 Efficacy and safety of 3 years of continuous ozanimod treatment: an interim analysis of the True North open-label extension study

Abstract Background The phase 3 True North (TN) study demonstrated the efficacy and safety of ozanimod over 52 weeks in patients with moderately to severely active ulcerative colitis (UC). Patients completing 52 weeks of TN were eligible for the ongoing TN open-label extension (OLE) assessing the long-term efficacy and safety of ozanimod. Presented is the interim analysis of the TN OLE in patients with approximately 3 years of continuous ozanimod treatment. Methods This analysis evaluated patients who achieved clinical response after receiving 52 weeks of continuous ozanimod 0.92 mg during TN and subsequently entered the TN OLE (data cutoff: 10 January 2022, the point at which the OLE Week 94 disposition was available for patients). Patient-reported (rectal bleeding and stool frequency) and clinician-reported (Physician’s Global Assessment) outcomes were collected. Centrally read endoscopy was performed at OLE Weeks 46 and 94 (98 and 146 weeks of continuous ozanimod treatment, respectively). Efficacy data (clinical remission, clinical response, endoscopic improvement, and corticosteroid-free remission) were evaluated in the intent-to-treat population at OLE Weeks 46 and 94 using observed case (OC) and nonresponder imputation (NRI) analyses. Partial Mayo scores (PMS) were assessed from TN baseline to OLE Week 94. Adverse events were monitored throughout TN and the subsequent OLE. Results In all, 131 patients entered the OLE after achieving clinical response following 52 weeks of continuous ozanimod during TN; at data cutoff, 87.0% completed OLE Week 46 (98 weeks of continuous ozanimod) and 71.8% completed OLE Week 94 (146 weeks of continuous ozanimod). Patients had a mean age of 44 years and 52% were female. Most (68%) had left-sided UC disease, 24% had concomitant corticosteroid use at TN baseline, and 32% had prior exposure to tumour necrosis factor inhibitors. Most patients achieved clinical remission, clinical response, corticosteroid-free remission, and endoscopic improvement at OLE Week 46 in the OC (Figure 1A) and NRI (Figure 1B) analyses. At OLE Week 94, 91.4% of patients achieved clinical response in the OC analysis (NRI, 56.5%). Ozanimod was associated with a reduction in mean PMS during TN (PMS=6.2 at Week 0 and 0.9 at Week 52), and this was sustained through OLE Week 94 (PMS=0.9) (Figure 2). No new safety findings emerged from this analysis. Conclusion This interim analysis of the TN OLE found that most of the patients who achieved clinical response after 1 year of ozanimod had sustained efficacy for an additional 2 years. No new safety signals were observed with long-term ozanimod use.

OP39 Safety of ustekinumab in IBD: Final pooled long-term safety analysis through 5 years in CD and 4 years in UC

Abstract Background Long-term efficacy of ustekinumab (UST) has been reported in Crohn’s disease (CD) through 5 years (yrs)1 and in ulcerative colitis (UC) through 4 yrs.2 A previous pooled analysis of long-term safety data reported a favorable UST safety treatment profile for inflammatory bowel disease (IBD).3 Here, we present results of the final cumulative analysis of long-term safety data from UST studies through up to 5 yrs in CD and 4 yrs in UC. Methods Data from 6 phase 2/3 UST IBD studies were pooled. In phase 3, patients (pts) received a single IV placebo (PBO) or UST (130mg or ~6mg/kg) induction dose followed by SC maintenance doses of PBO or UST (90mg q8w or q12w). Concomitant immunomodulators and corticosteroids were permitted. All pts who received ≥1 dose of UST were included. Safety outcomes are summarized and presented using number of events per 100 patient-years (PY) of follow-up and corresponding 95% confidence interval (CI). Results In this final pooled UST IBD safety data, 2575 pts were treated with UST with 4826 PYs of follow-up. Rates of key safety events, including MACE and malignancies, were similar between PBO and UST or not higher for UST (Table 1). The most frequently occurring adverse events (AEs) in either group (excluding diseases under study) were headache (PBO 16.66 vs. UST 11.60), arthralgia (PBO 15.91 vs. UST 11.23), abdominal pain (PBO 13.79 vs. UST 9.86), nausea (PBO 11.35 vs. UST 7.13), and pyrexia (PBO 11.35 vs. UST 5.91); infections were nasopharyngitis (PBO 17.82 vs UST 19.10) and upper respiratory tract infection (PBO 11.78 vs UST 9.80). The most frequently reported serious infections of anal abscess, pneumonia, cellulitis, and abdominal abscess were no higher in the UST group than PBO, except gastroenteritis (PBO 0.11 vs UST 0.25). No lymphomas were reported. Nine deaths were reported in UST-treated pts (0.00 [0.00, 0.32] PBO vs. 0.19 [0.09, 0.35] UST), 6 in CD and 3 in UC (all considered unrelated to study agent). Conclusion The final compilation of cumulative UST IBD safety data through 5 yrs in CD and 4 yrs in UC showed a safety profile that continued to be favorable and supports the well-established UST safety experience across all approved indications.

P498 Ustekinumab Real World Evidence Study (UndieS): study design with information about positioning and the choice of ustekinumab

Abstract Background Strict eligibility criteria of phase 3 trials limit the external validity of their results. Well-designed real-world studies are intended to complement these by describing the effectiveness and safety of these medicines in routine clinical practice. As therapeutic options for the treatment of Crohn’s disease (CD) expands, the ideal sequence of medications, and the influences on this, needs defining. Methods UndieS is a phase IV, multi-centre, prospective, observational study of patients with CD initiated on ustekinumab as part of their routine care. 600 participants will be recruited from 22 centres across the UK with a follow-up period of 2 years. Assessments at baseline and weeks 8, 16/20, 56, 80 and 104 include modified Harvey-Bradshaw Index (mHBI), IBD-Control, Treatment Satisfaction Questionnaire for Medication and PRO-2. The primary outcome is steroid-free remission (mHBI ≤ 4) at one year. Secondary outcome measures include describing changes in disease activity, PROs and tolerability. Results Recruitment started in March 2020 with 437 patients recruited so far. The summary baseline characteristics are 50% male, median (range) age at consent 41 (18-91) years (14% > 65 years), median mHBI 5 (0-39). The median duration of Crohn’s disease before starting ustekinumab was 8 (0-60) years. Disease location (as per Montreal classification) is: L1: 35%, L2: 20%, L3: 44% and isolated L4: 1%. 24% of participants reported perianal disease. The proportion of participants using concomitant immunomodulators or oral corticosteroids on starting ustekinumab (15% and 11% respectively) is lower than in the UNITI clinical trial program. 59% of participants had a disease activity score suggesting that they would not meet the threshold required for entry into UNITI and suggested by NICE for moderately-to-severely active CD, although 81% of these had evidence of inflammation. Inadequate response to or adverse effects from a previous treatment was a common indication (52% of participants). 32% of the participants are bio-naïve; 64% and 10% have previous exposure to anti-TNF and vedolizumab respectively and 6% have been exposed to both. Details of prior biologic exposure is shown in figure 1. The most common reasons for the specific choice of ustekinumab were intolerance to immunomodulators and concern about infection risk. Bio-naïve patients were older (median 45 vs. 39 years; p=0.02) and had a shorter disease duration (7 vs. 9 years; p=0.04) than those with prior biologic exposure. Conclusion Our cohort is representative of those patients with CD being treated with ustekinumab in a real-world setting. Some important differences between these patients and those recruited to phase 3 clinical trials are identified.

P478 Platelet-related indicators for predicting vedolizumab response in patients with Ulcerative Colitis

Abstract Background Ulcerative Colitis (UC) combine both inflammation and coagulation in their pathogenesis and clinical manifestations. Although platelets (PLT) are well known for their role in hemostasis, there are a rising number of studies supporting their considerable role as inflammatory amplifiers in chronic inflammatory conditions. However, whether PLT are related to the efficacy of biologic agents is unknown. This study aimed to investigate whether platelet ratio before and after induction therapy can be predictive biomarkers for the therapeutic outcomes of vedolizumab therapy in UC. Methods Patients with moderate-to-severe UC receiving vedolizumab in our hospital between November 2020 and November 2022 were retrospectively evaluated. Patients with concomitant corticosteroid treatment≥20 mg, immunomodulators, or other conditions that could modify the platelet count were excluded. The primary endpoint was clinical response at the end of the induction period (at 14 weeks). We analyzed the association between platelet count, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), C-reactive protein (CRP), fecal calprotectin, and the clinical efficacy of vedolizumab. The above indicators between the response and nonresponse groups were compared via a univariate analysis. The independent risk factors of nonresponse were identified via a multivariate analysis. Results Seventy-one patients with moderate-to-severe active UC started treatment with vedolizumab and 20 patients (28.2%) experienced loss of response (LOR) after induction therapy. The platelet count, albumin, CRP, NLR, PLR, MLR, and Particul Mayo score between the LOR and response groups significantly differed. The Platelet ratio before and after induction therapy cut-off value of 1.077 was predictive of LOR, using receiver operating characteristic analysis (sensitivity:78.0%, specificity:81.8%). A univariate analysis revealed a significant relationship between LOR and the platelet ratio (P＜0.05). Multivariate analysis indicated the platelet ratio as an independent prognostic factor for LOR (OR=11.219, 95% CI:3.316-37.959, P＜0.05). Conclusion Platelet ratio before and after induction therapy is a useful prognostic marker in patients with moderate-to-severe active UC treated with vedolizumab, and may contribute to appropriate use of vedolizumab LOR. A large sample from multiple centers is needed to validate the association between platelet-related measures and the rate of vedolizumab response.

P421 Real-world effectiveness and safety of vedolizumab induction therapy for Crohn’s disease in Poland – a prospective, observational POLONEZ II study considering patients reported outcomes

Abstract Background Vedolizumab (VDZ) is a gut-selective anti-lymphocyte trafficking drug, used to treat ulcerative colitis (UC) and Crohn’s disease (CD), lifelong conditions with unknown aetiology with frequent relapses and remitting course which are a burden for patients and a challenge for health care systems. We aimed to evaluate the real-world effectiveness of VDZ induction therapy for Polish patients with CD. Methods This was a multicenter, observational, prospective study involving patients with moderately to severely active CD qualified for reimbursed treatment with VDZ in 10 Polish centers between Apr 2020 and Nov 2021. The primary endpoints were clinical response (≥ 70-point reduction in Crohn's Disease Activity Index, CDAI) and remission rate (CDAI ≤ 150) at week 14. Other endpoints included changes from baseline (week 0, first dose of VDZ) to week 14 for patient-reported outcomes (PROs): quality of life (Inflammatory Bowel Disease Questionnaire, IBDQ), fatigue (Inflammatory Bowel Disease-Fatigue Self-assessment Scale, IBD-F), stool frequency (SF score) and abdominal pain score (APS). Results A total of 98 patients with CD were enrolled in the study. At baseline, the most common disease location in the cohort was ileocolonic CD (n=70/98, 72.9%). Fifty patients (51%) were on corticosteroids at week 0. Nine patients discontinued VDZ therapy before or at week 14, mainly due to lack of response (n=6/9, 66.7%). At week 14, 63.3% of patients (n=62/98) achieved clinical remission and 30% (n=15/50) steroid-free remission. Clinical response rate in overall study population was 90.8% (n=89/98). Median CDAI score decreased from 336.5 to 108.0 (p<0.001) at week 14 (Fig. 1). Declines from baseline were also observed in median CDAI sub-scores: SF score (38.0 vs 10.0; p<0.001) and APS (18.0 vs 2.0; p<0.001) (Fig. 1). At week 14, median changes from baseline scores on the IBDQ (total and all subscales) were statistically significant (p<0.001) (Fig. 2). Improvement was also observed after the VDZ 14-week treatment period in fatigue severity and frequency (p<0.01) as well as its impact on daily activities (p<0.001) based on IBD-F (Fig. 3). The percentage of patients without concomitant corticosteroids increased more than 1.5-fold from week 0 (49.0%) to week 14 (76.3%). Conclusion VDZ is effective in induction therapy and has significant impact on disease activity and Health-Related Quality of Life (HRQL) including fatigue in patients with CD.

P588 Interim results from the randomised VERDICT trial to determine the optimal treatment target in patients with ulcerative colitis

Abstract Background The optimal treatment target for ulcerative colitis (UC) is uncertain. The VERDICT trial in moderate to severe UC aims to determine if a treatment target of corticosteroid (CS)-free symptomatic + endoscopic + histologic remission is superior to CS-free symptomatic remission alone. Trial progress and the study cohort to date are described herein. Methods Our aim is to enrol 660 patients with moderately to severely active UC (Mayo rectal bleeding subscore [RBS] ≥1; Mayo endoscopic score [MES] ≥2). Patients are randomised to 3 treatment targets (2:3:5 ratio): CS-free symptomatic remission (Mayo RBS = 0) (Group 1); CS-free endoscopic remission (MES ≤1) + symptomatic remission (Group 2); or CS-free histologic remission (Geboes score <2B.0) + endoscopic + symptomatic remission (Group 3). Therapy is administered according to a treatment algorithm that is dependent upon each patient’s UC treatment at screening. Early introduction of vedolizumab (VDZ) and dose escalation up to 300 mg every 4 weeks until the target is met are central to each algorithm. Up to 3 opportunities to achieve the assigned target were prespecified in the algorithms (weeks 16, 32, or 48). Patients and central readers for endoscopy/histopathology are blinded to group allocation, and investigators are unblinded. Results As of 2 November 2022, 331 patients were enrolled at 55 sites across 10 North American and European countries. Mean (SD) baseline characteristics (Table) include a UC duration of 8.6 (8.3) years, Mayo Clinic score of 8.7 (1.7), C-reactive protein level of 13.3 (15.6) mg/dL, and a faecal calprotectin level of 1462.3 (1481.3) mg/kg. At baseline, 52% (172/331) and 11% (37/331) of patients were receiving concomitant CS and immunosuppressives, respectively, and 14% (47/331) had current/prior exposure to tumour necrosis factor antagonists. Most patients (85%) were receiving nonbiologic therapy. Of all randomised patients, 43/69 (Group 1), 65/98 (Group 2), and 115/164 patients (Group 3) have reached week 16; and 28 (65%), 25 (39%), and 42 (37%) met their target, respectively. After a median of 35 weeks (IQR 18-53), a total of 30 (Group 1), 32 (Group 2), and 50 patients (Group 3) have met their target and will be followed to relapse or study termination. The serious adverse event rate (8%; 36/483) was similar across groups. Conclusion VERDICT has randomised ~50% of its target enrolment. Enrolled patients represent a typical moderate to severe UC population and are primarily bionaive and receiving early VDZ initiation. Early results suggest the feasibility of achieving each treatment target, specifically histologic remission, and are consistent with expected values. No new VDZ safety signals were identified. Completion of enrolment is anticipated in late 2023.

329 Efficacy and safety of dupilumab treatment with concomitant topical corticosteroids in children aged 6 months to 5 years with severe atopic dermatitis

Abstract There are limited approved systemic treatment options for children with atopic dermatitis (AD). Dupilumab is now approved in the United States for patients 6 months and older with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies. European Medicines Agency is evaluating the use of dupilumab in children aged 6 months through 5 years with severe AD only. To report the efficacy and safety of dupilumab in the subgroup of children aged 6 months to 5 years with severe AD (IGA score = 4) at baseline in the LIBERTY AD PRESCHOOL trial (NCT03346434 part B). Patients aged 6 months to 5 years with inadequately controlled moderate-to-severe AD were enrolled in LIBERTY AD PRESCHOOL (part B), a randomized, double-blind placebo-controlled phase 3 study. Patients were randomized to either dupilumab 200/300 mg every 4 weeks (200 mg if baseline weight 5 to <15 kg, 300 mg if 15 to <30 kg) or placebo for 16 weeks. All patients initiated standardized treatment with low-potency topical corticosteroids (TCS) from day –14. This analysis reports efficacy and quality-of-life endpoints including a 75% reduction from baseline in the Eczema Area and Severity Index (EASI-75), Peak-Pruritus Numerical Rating Scale (PP-NRS), Children’s Dermatology Life Quality Index (CDLQI, for children aged 4 to <6 years), and Infant’s Dermatitis Quality Of Life (IDQOL, for children <4 years) in children with severe AD. Of the total trial population of 162 patients with moderate-to-severe AD, 125 patients with severe AD at baseline were randomized: 63 to the dupilumab + TCS treatment group and 62 to the placebo + TCS treatment group. Baseline demographics were similar. Mean (SD) baseline disease characteristics were also similar between the dupilumab and placebo groups: EASI (38.8 [13.7] vs. 35.4 [12]), body surface area (63.1% [21] vs. 58.9% [21.4]), weekly average PP-NRS (7.6 [1.4] vs. 7.6 [1.6]), CDLQI (17.5 [5.5] vs. 17.8 [6.4]) and IDQOL (18.4 [5.1] vs. 17.4 [5.4]). Dupilumab treatment resulted in a rapid and significant increase in the proportion of patients achieving EASI-75 compared with placebo treatment by week 4 (27% vs. 4.8%; P = 0.0009). By week 16, this improvement was further increased compared with the placebo group (46% vs. 7%; P < 0.0001). At week 16, dupilumab-treated patients had a significantly greater percent reduction from baseline in PP-NRS compared with the placebo group (LS mean (SE)–41.8 [5.4] vs. 0.5 [5.4]; P < 0.0001). Dupilumab also resulted in significant improvement in quality-of-life outcomes compared with placebo (LS mean [SE]) change from baseline to week 16 in CDLQI (−9.1 [1.1] vs. −2.6 [1.2]; P < 0.0001); IDQOL (−9.1 [1.3] vs. −0.6 [1.1]; P < 0.0001). Treatment-emergent adverse events (TEAEs) were reported in 42 (66.7%) patients in the dupilumab group and 45 (73.8%) patients in the placebo group. Most TEAEs were mild to moderate and deemed unrelated to the study drug by the investigator. The most common TEAE was atopic dermatitis in both the dupilumab group (10 [15.9%]) and placebo group (16 [26.2%]). Additionally, TEAEs in the conjunctivitis cluster were reported by 4 (6.4%) patients in the dupilumab group and none in the placebo group. In the placebo group, 3 (4.9%) serious adverse events were reported. No dupilumab-related adverse events were serious or led to treatment discontinuation. Dupilumab significantly improved AD signs, symptoms, and quality of life in children aged 6 months to 5 years with severe AD. The safety profile was consistent with that previously seen in adults, adolescents, and children aged > 6 years of age.

337 Dupilumab treatment is not associated with an increased overall risk of infections in patients aged 6 months to 5 years with moderate-to-severe atopic dermatitis

Abstract Patients with atopic dermatitis (AD) have an increased risk of infection, including skin infections. Previous studies in children aged 6–11 years and adolescents showed that dupilumab is not associated with an increased risk of overall infections and is associated with a lower incidence of skin infections compared with a placebo. This post-hoc analysis reports the impact of dupilumab treatment on infections, including skin infections, in children aged 6 months to 5 years with moderate-to-severe AD. In LIBERTY AD PRESCHOOL, a double-blind, placebo-controlled trial (NCT03346434, part B), children aged 6 months to 5 years with moderate-to-severe AD (Investigator’s Global Assessment score ≥3) were randomized 1 : 1 to subcutaneous dupilumab every 4 weeks (200 mg if baseline weight was ≥5 to <15 kg, 300 mg if weight was ≥15 to <30 kg) or placebo with concomitant low-potency topical corticosteroids for 16 weeks. Exposure-adjusted rates (patients with ≥1 event per 100 patient-years [nP/100 PY]) and systemic anti-infective medication use (nP/100PY) were used to compare treatment groups. 162 patients were randomized to dupilumab (n = 83) or placebo (n = 79). During the 16-week treatment period, total infections rates were numerically lower in the dupilumab-treated group (nP/100PY: 185.2) compared with the placebo-treated group (nP/100PY: 245.7). Fewer infections of skin-structure and soft tissues were reported in the dupilumab group (nP/100PY: 24.7) compared with the placebo group (nP/100PY: 40.2). Dupilumab-treated patients had significantly lower rates of non-herpetic skin infections (nP/100PY: 42.7) than placebo-treated patients (nP/100PY: 92.7; P < 0.05 vs. placebo). There was no significant difference in rates of herpetic skin infections between the dupilumab (nP/100PY: 20.0) and placebo groups (nP/100PY: 17.1; P = 0.817 vs. placebo). No helminthic infections were reported in either group. Systemic anti-infective medication use was significantly less frequent in the dupilumab group (nP/100PY: 104.7) compared with placebo (nP/100PY: 203.0; P < 0.05 vs. placebo). The overall safety of dupilumab was consistent with the known safety profile. Dupilumab treatment is associated with lower overall infections and significantly lower non-herpetic skin infections than placebo in children aged 6 months to 5 years with moderate-to-severe AD.

340 Dupilumab treatment of children with moderate-to-severe atopic dermatitis increases bone alkaline phosphatase, a marker of bone mineralization

Abstract Children with atopic dermatitis (AD) are at risk for low bone mineral density (BMD), which is associated with an increased prevalence of osteopenia, osteoporosis, and fracture risk.1,2 Factors such as restricted nutrition, vitamin D deficiency, poor sleep and corticosteroid use contribute to lower bone alkaline phosphatase (BALP) levels, a marker of bone mineralization, seen in children with moderate-to-severe AD compared with healthy children.3 A major determinant for the lifetime risk of fractures and osteoporosis is the magnitude of peak bone mass achieved during prepubescent years. Low BALP and BMD in children with moderate-to-severe AD could contribute to a higher prevalence of osteopenia and osteoporosis. The objective of this analysis is to report the impact of dupilumab treatment on markers of bone formation in children aged ≥ 6 to < 12 years with moderate-to-severe AD. The analysis was performed retrospectively on sera from participants in LIBERTY AD PEDS (NCT03345914) and LIBERTY AD PED-OLE (NCT02612454). In LIBERTY AD PEDS, a double-blind, 16-week, phase 3 trial, children aged 6 to < 12 years were randomized 1 : 1 : 1 to 300 mg dupilumab every 4 weeks (300 mg q4w), a weight-based regimen of dupilumab every 2 weeks (100 mg q2w for patients with baseline weight <30 kg, and 200 mg q2w for those with baseline weight ≥30 kg), or placebo; with concomitant medium-potency topical corticosteroids (TCS). After the initial 16-week trial, children aged 6 to <12 years were enrolled in the open-label extension study LIBERTY AD PED-OLE. Patients received dupilumab 300 mg q4w, which could be titrated up in case of inadequate clinical response at week 16 (200 mg q2w for patients with baseline weight <60 kg, and 300 mg q2w for those with baseline weight ≥60 kg); with concomitant medium-potency TCS. Bone biomarkers including BALP, procollagen type 1 N-terminal propeptide, C-terminal crosslinking telopeptide of type 1 collagen, osteocalcin, and insulin-like growth factor 1 were analysed at baseline, 8, 12, 16 and BALP only at 52 weeks. Dupilumab treatment led to a rapid and significant increase in geometric mean (standard error) levels of BALP in children with moderate-to-severe AD at 16 weeks compared with patients in the placebo group (77.7(1.02) μgL−1 vs. 65.0(1.04) μgL−1; P < 0.0001). As well as a rapid and significant increase in BALP levels in children from the placebo group once they joined the OLE trial. BALP levels increased over 52 weeks in all treated children, reaching a level of 78–84 μgL−1 which constitutes a significant improvement compared with baseline, and is comparable to healthy reference intervals. An increasing trend from baseline to 16 weeks of dupilumab treatment was observed for other biomarkers, however, there was a limited number of data points due to insufficient volumes of serum available for analysis. These placebo-controlled results show, for the first time, a rapid and significant increase in BALP, and a possible trend in other biomarkers, in children with AD during treatment with dupilumab. These results suggest increased bone mineralization during the treatment period.

335 Improvement in sleep quality, anxiety and depression in adults with moderate-to-severe atopic dermatitis with dupilumab treatment

Abstract Sleep disturbance is considered one of the most prevalent symptoms of atopic dermatitis (AD), and is associated with daytime sleepiness, anxiety and depression. In previous phase 3 trials, dupilumab treatment demonstrated significant improvement in objective AD signs and severity of symptoms, including sleep disturbance and mental health symptoms. To investigate the effect of dupilumab for up to 24 weeks on sleep quality, daytime sleepiness, anxiety and depression, using data from the DUPISTAD (NCT04033367) study. The randomized, phase 4 DUPISTAD study, was divided into two 12-week periods: an initial double-blind placebo-controlled period, and a subsequent 12-week open-label extension (OLE) period. The 24-week study enrolled adult patients with moderate-to-severe AD (Eczema Area and Severity Index score ≥12, Peak Pruritus Numeric Rating Scale [NRS] score ≥3, Sleep Disturbance NRS average score ≥5) who showed an inadequate response to topical treatments. These patients were randomized 2 : 1 to dupilumab 300 mg every 2 weeks (q2w) for both the double-blind and OLE periods or placebo for the initial double-blind period, followed by dupilumab 300 mg q2w for the OLE period. The use of concomitant topical corticosteroids was permitted as needed by both groups throughout the study. Endpoints included mean change from baseline to week 24 for Patient-Reported Outcome Measures Information System (PROMIS) Sleep T-score (standardized score ranging from 30 [best] to 80 [worst], with a mean of 50), Epworth Sleepiness Scale (ESS; scored 0–24; higher values indicate increased daytime sleepiness), and Hospital Anxiety and Depression Scale (HADS; scored 0–21; higher values indicate a worse outcome). Throughout the study, patients also completed a Sleep Diary, recording the NRS of restfulness upon waking up (scored 0–10; lower values indicate a worse outcome). Statistical comparisons were not performed on the data collected during the OLE observation period. A total of 188 patients were enrolled in the study: 127 received continuous dupilumab (dupilumab–dupilumab group) and 61 received placebo to week 12 and then dupilumab to week 24 (placebo–dupilumab group). Baseline demographics and disease characteristics were well balanced. Improvement from baseline in sleep quality, daytime sleepiness, anxiety and depression was observed at week 24 in both groups, as illustrated by the mean change from baseline in PROMIS Sleep T-scores (−12.5 in the dupilumab–dupilumab group and −11.7 in the placebo–dupilumab group), ESS scores (−4.6 in the dupilumab–dupilumab group and −3.7 in the placebo–dupilumab group), HADS anxiety scores (−3.8 in the dupilumab–dupilumab group and −4.4 in the placebo–dupilumab group), HADS depression scores (−4.4 in the dupilumab–dupilumab group and −3.4 in the placebo–dupilumab group), and the NRS of restfulness upon a waking-up item of the Sleep Diary (+3.3 in the dupilumab–dupilumab group and +3.4 in the placebo–dupilumab group). The improvement achieved by the placebo–dupilumab group converged with that of the dupilumab–dupilumab group during the OLE period, as shown by the mean change from week 12 to week 24 in PROMIS Sleep T-score (−3.8), ESS score (−1.9), HADS anxiety score (−1.6), HADS depression score (−0.9) and NRS of restfulness upon a waking-up item of the Sleep Diary (+1.5). The safety profile of dupilumab was consistent with the known safety profile. Dupilumab provided sustained improvement through 24 weeks in patient-reported measures of sleep, daytime sleepiness, anxiety, and depression in adult patients with moderate-to-severe AD. Patients who were switched from placebo to dupilumab at week 12 showed rapid improvement in these parameters after the switch, eventually matching the improvement achieved by patients who received dupilumab from baseline through week 24.

332 Improvement in symptoms of atopic dermatitis (AD) and AD-related quality of life with dupilumab treatment in adults: 24-week results of the DUPISTAD study

Abstract Atopic dermatitis (AD) is a chronic disease characterized by sleep disturbance, associated with night-time itching and scratching, along with skin pain, resulting in daytime drowsiness, diminished daytime productivity and overall reduced quality of life (QoL) in patients with AD. To report the effect of up to 24 weeks of dupilumab treatment on the QoL of adult patients with moderate-to-severe AD, using data from the DUPISTAD (NCT04033367) study. Phase 4, a randomized DUPISTAD study, comprised two 12-week periods: an initial placebo-controlled double-blind period, and a subsequent 12-week open-label extension (OLE) period. Adult patients with moderate-to-severe AD (Eczema Area and Severity Index score ≥12, Peak Pruritus Numeric Rating Scale [NRS] score ≥3, Sleep Disturbance NRS average score ≥5), showing an inadequate response to topical treatments, were randomized 2 : 1 to dupilumab 300 mg every 2 weeks (q2w) for both the double-blind and OLE periods or placebo for the initial double-blind period, followed by dupilumab 300 mg q2w for the OLE period. The use of concomitant topical corticosteroids was permitted during the entire course of the study. Endpoints, including Patient-Oriented Eczema Measure (POEM; scored 0–28, with higher values indicating a worse outcome), Dermatology Life Quality Index (DLQI; scored 0–30, with higher values indicating a poorer QoL), Skin Pain and Sensitivity NRS (scored 0–10, where 0 = no pain/normal sensitivity and 10 = worst possible pain/extremely sensitive) were assessed from baseline to week 24. The enrolled patients also completed a Work Productivity and Activity Impairment Questionnaire (WPAI-AD), including an NRS rating of the AD-Affected Ability to do Regular Daily Activities other than a Job (scored 0–10, where 0=‘no effect’ and 10=‘prevented me from doing my daily activities’). Formal statistical comparisons were not performed on the data resulting from the OLE period. The DUPISTAD study enrolled a total of 188 patients: 127 patients received dupilumab throughout (dupilumab–dupilumab group), and 61 patients received a placebo and then switched to dupilumab (placebo–dupilumab group). Baseline demographics and disease characteristics were well balanced. Improvement from baseline in AD-related patient-reported QoL indicators and AD symptoms was observed at week 24 in both groups, as illustrated by the mean change from baseline in POEM total scores (−14.6 in the dupilumab–dupilumab group and −15.9 in the placebo–dupilumab group), DLQI scores (−12.6 in the dupilumab–dupilumab group and −13.4 in the placebo–dupilumab group), Skin Pain NRS scores (−4.7 in the dupilumab–dupilumab group and −5.0 in the placebo–dupilumab group), Skin Sensitivity NRS scores (−4.6 in the dupilumab–dupilumab group and −5.0 in the placebo–dupilumab group), and the WPAI-AD NRS of Ability to do Regular Daily Activities scores (−4.2 in the dupilumab–dupilumab group and −3.8 in the placebo–dupilumab group). The placebo–dupilumab group experienced most of this improvement during the OLE period, as illustrated by the mean change from week 12 to week 24 in POEM total score (−11.5), DLQI score (−5.5), Skin Pain NRS score (−3.0), Skin Sensitivity NRS score (−3.0) and the WPAI-AD NRS of Ability to do Regular Daily Activities score (−2.0). The safety profile of dupilumab was consistent with the known safety profile. Dupilumab provided sustained improvements through 24 weeks in AD-related patient-reported measures of QoL and AD symptoms in adults with moderate-to-severe AD. Patients who were switched from placebo to dupilumab at week 12 showed rapid improvement in these parameters after the switch, eventually matching the improvement achieved by patients who received dupilumab from baseline through week 24.

Steroid-sparing effect of ciclosporin A 1 mg/mL: 5-year case series of 107 children and young people with vernal keratoconjunctivitis

Background/aimsTo explore the steroid-sparing and other therapeutic effects of ciclosporin A (CsA) 1 mg/mL in the management of vernal keratoconjunctivitis (VKC).MethodsOpen retrospective single-group interventional consecutive cohort study (case series) of...

417 Dupilumab Significantly Improves Sleep Disturbance in Adults with Moderate-to-Severe Atopic Dermatitis: Results of the DUPISTAD study

DUPISTAD (NCT04033367) evaluated the impact of dupilumab on sleep. Adults with moderate-to-severe AD (EASI ≥12, Pruritus numerical rating scale (NRS) ≥ 3 and sleep NRS ≥5) were randomized 2:1 to dupilumab 300mg every 2 weeks (q2w) or placebo for 12 weeks (W12); both groups were permitted concomitant topical corticosteroids. The primary efficacy endpoint was sleep quality percentage change from baseline to W12, assessed by 11-point sleep NRS. Secondary endpoints included percent change in peak pruritus NRS, change in SCORing AD (SCORAD), SCORAD sleep visual analog scale (VAS), EASI and the Patient-Reported Outcomes Measurement Information System sleep-impairment SF8a score (PROMIS-T).

Cognitive Impairment Among Patients with Chronic Immune Thrombocytopenia

Introduction: Immune thrombocytopenia (ITP) is an autoimmune disease associated with autoantibody-mediated platelet destruction and impaired platelet production, resulting in thrombocytopenia and high bleeding risk. Fatigue and impairment of both memory and concentration are also common in ITP, theoretically due to acute neural inflammation, microbleeding, and thrombotic occlusions of small blood vessels in the brain. However, little is known about the nature and severity of cognitive impairment in patients with chronic ITP. Tests from the Cogstate Brief Battery (CBB) and composite scores computed from these have a high sensitivity to cognitive dysfunction in clinical and clinical trial contexts. The aim of this analysis was to assess cognitive impairment among difficult-to-treat patients with ITP. Methods: Participants (N=60) in the ongoing, global phase 1/2 study (NCT03395210) assessing the safety and efficacy of the Bruton tyrosine kinase inhibitor rilzabrutinib in ITP, were eligible for cognitive testing at baseline. In the CBB, the Detection test (DET) measured psychomotor function, the Identification test (IDN) measured attention, the One Card Learning test (OCL) measured visual learning, and the One Back test (ONB) measured working memory. For each participant, prior to rilzabrutinib treatment, the score on each test was compared with age-matched normative data to produce a standardized score (Z-score). Z-scores measure the distance between an observed value and a reference mean using standard deviation units and can be positive or negative, indicating that the observed value lies above or below the mean, respectively. Z-scores ≤-1 denoted impairment. Descriptive summary statistics, including mean Z-scores for individual tests and composite cognitive scores (Psychomotor/Attention, Learning/Memory), and level of impairment are presented. Relationships between cognitive impairment and demographics, concomitant medication, and medical history were also explored. Results: At baseline, the 49 patients with CBB assessments had a mean age of 50 years, 57% were females, and 71% had an ITP duration of ≥3 years; 14 patients each had concomitant corticosteroids or thrombopoietin receptor agonists (TPO-RA) and 7 patients had both concomitant therapies. Medical history included hypertension (n=17), depression/anxiety (n=8), diabetes (n=7), and stroke/CNS bleeding (n=1). Mean Z-scores for the psychomotor function, attention, and working memory tests were below age-matched healthy norms (Table 1). The degree of impairment was substantial for the psychomotor function and attention tests and composite scores. Impairment was also large for the working memory test, whereas performance on the visual learning test was close to normal. The level of impairment followed the same pattern, with top rates for the attention (67% of patients), followed by psychomotor function (53% of patients), working memory (39% of patients), and visual learning (16% of patients) tests. Psychomotor/Attention impairment was greater (69% of patients) than Learning/Memory (43% of patients; Table 1) and occurred irrespective of biological/clinical characteristics (Figure 1). More than half of patients aged <65 years, with no concomitant ITP medication, and those with no medical history had a "Clinically Important Cognitive Impairment". Conclusion: This report provides evidence of cognitive impairment in patients with ITP. The cognitive impairment was moderate in magnitude for Psychomotor/Attention, and mild for Learning/Memory. Further, the observed impairment appeared to be irrespective of biological/clinical characteristics and unrelated to concomitant use of corticosteroids or TPO-RA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Itacitinib and Corticosteroids As Initial Treatment for Chronic Graft-Versus-Host Disease: Phase 1/2 Results from Gravitas-309

Background: Itacitinib is a potent, selective oral Janus kinase (JAK) 1 inhibitor with broad anti-inflammatory activity. GRAVITAS-309 was designed as a 2-part, multicenter, randomized trial to assess the efficacy and safety of itacitinib in combination with corticosteroids (CS) as first-line treatment for moderate or severe chronic graft-versus-host disease (GVHD). We describe preliminary results from the open-label, dose-finding portion of the study. Methods: The study initially investigated itacitinib at doses of 200 mg once daily (qd; n=11) and 300 mg qd (n=10) in combination with CS. Both doses were well tolerated. The trial was then expanded to test itacitinib 400 mg qd and 300 mg twice daily (bid); the initial 300-mg qd cohort was expanded, and a CS monotherapy cohort was added (Figure 1). The expected CS starting dose was 0.5-1 mg/kg per day prednisone (or methylprednisolone equivalent) with a dose taper initiated on Day 14 or earlier during the second week of treatment and following published recommendations (Flowers and Martin. Blood. 2015;125[4]:606-15). Itacitinib dosage was initially reduced by 100 mg when given concomitantly with a strong CYP3A4 inhibitor (sCYP3A4i; eg, azole antifungals). A total of 140 patients (pts) (35/treatment group) with moderate or severe chronic GVHD were to be randomized 1:1 using chronic GVHD risk status (moderate vs severe) as a stratification factor. The primary objective was to identify the appropriate dose and schedule of itacitinib for further development. The data cutoff was January 31, 2022. Results: 103 pts were enrolled and received at least one dose of itacitinib. The cohorts were well balanced for pt and disease characteristics. Median age was 57 years (range, 23-76) for the itacitinib cohorts and 59 years (range, 28-75) for the CS cohort. Approximately two-thirds of pts had moderate chronic GVHD. At the time of data cut, 39 (38%) pts in the itacitinib cohorts and 10 (28%) pts in the CS cohort continued study treatment. Median duration of study treatment was 27-28 weeks for the itacitinib cohorts (including 13-16 weeks of concomitant CS) and 17 weeks for the CS cohort. The itacitinib 300-mg bid dose cohort was discontinued early due to malignancy relapse occurring in 4/29 (14%) pts and more pts requiring dose reductions compared with the 400-mg qd and 300-mg qd cohorts (28% vs 17% and 8%, respectively), mostly due to cytopenias. Incidence of grade ≥3 treatment-emergent adverse events (AEs) was higher in the itacitinib cohorts than with CS (65% vs 31%) and were reported most commonly in the system organ classes of infections (44% vs 6%) and blood and lymphatic system disorders (23%-34% vs 6%). Cytomegalovirus (CMV) infections occurred in 10%-15% of pts in itacitinib cohorts (including CMV pneumonia [n=3], esophagitis [n=1], enteritis [n=1]) vs 3% with CS. The all-cause mortality rate was 14%-18% in itacitinib cohorts vs 11% with CS, with infections the leading cause. The overall response rate (ORR) at 6 months was 46% (complete response [CR], 14%) with 300-mg qd and 53% (CR, 32%) with 400-mg qd, vs 36% (CR, 18%) with CS. A preliminary exposure-response analysis showed a bell-shaped curve with maximum efficacy decreasing at higher exposures, consistent with increasing incidence of AEs. 60%-70% of patients received coadministration with a sCYP3A4i at any time point during study treatment, which increased itacitinib exposure across all doses, requiring dose reduction by 200 mg qd. Conclusion: Preliminary results for first-line treatment of moderate or severe chronic GVHD showed an increase in ORR and CR rate with itacitinib + CS vs CS alone in both the 300-mg qd and 400-mg qd cohorts, at the expense of increased rates of cytopenias, infections, and mortality. This benefit:risk ratio does not support moving the combination of itacitinib + CS to a later phase of development in first-line therapy of chronic GVHD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Topical cyclosporine A 1mg/ml for atopic keratoconjunctivitis: Five-year case series of 99 children and young people.

To explore the effects of cyclosporine A (CsA) in the management of atopic keratoconjunctivitis (AKC). Open single-group interventional consecutive cohort study (case series) at a single eye care facility in the UK. We reviewed the electronic patient records of 99 children and young people (CYP) aged 3.4-18 years with AKC treated with topical CsA 1mg/ml. Main outcome measures were number of prescriptions and hospital clinic visits over 12 months before and after the start of CsA and the proportion of CYP affected by adverse effects. The median number of inflammatory episodes requiring treatment with topical corticosteroids (tCS) fell from 3 (interquartile range IQR 1-4) during the 12 months prior to CsA to 1 (IQR 0-3) during the 12 months after, excluding tCS prescriptions with the first CsA prescription (Wilcoxon signed ranks test, 2 tailed, p< 0.01). In the 12-month period following initiation of CsA 1mg/ml with concomitant prescription of tCS (n= 66), daily dosage of steroids was reduced in 62 CYP (93.9%), and they were discontinued in 43 (65.2%). The median number of hospital visits fell from 4 (IQR 3-6) to 3 (IQR 2-5; Wilcoxon p< 0.01). Adverse events leading to discontinuation of CsA were stinging (instillation site pain; 9/99, 9%) and a transient skin rash (1/99, 1%). Off-label use of commercial preparations of CsA 1mg/ml significantly reduces the need for concomitant topical corticosteroids and hospital clinic visits in CYP with AKC. Stinging and skin rash can lead to discontinuation.

First-in-Class Small Molecule to Inhibit CYP11A1 and Steroid Hormone Biosynthesis.

Binding of steroid hormones to their cognate receptors regulates the growth of most prostate and breast cancers. We hypothesized that CYP11A inhibition might halt the synthesis of all steroid hormones, because CYP11A is the only enzyme that catalyses the first step of steroid hormone biosynthesis. We speculated that a CYP11A inhibitor could be administered safely provided that the steroids essential for life are replaced. Virtual screening and systematic structure-activity relationship optimization were used to develop ODM-208, the first-in-class, selective, nonsteroidal, oral CYP11A1 inhibitor. Safety of ODM-208 was assessed in rats and Beagle dogs, and efficacy in a VCaP castration-resistant prostate cancer (CRPC) xenograft mouse model, in mice and dogs, and in six patients with metastatic CRPC. Blood steroid hormone concentrations were measured using liquid chromatography-mass spectrometry. ODM-208 binds to CYP11A1 and inhibited its enzymatic activity. ODM-208 administration led to rapid, complete, durable, and reversible inhibition of the steroid hormone biosynthesis in an adrenocortical carcinoma cell model in vitro, in adult noncastrated male mice and dogs, and in patients with CRPC. All measured serum steroid hormone concentrations reached undetectable levels within a few weeks from the start of ODM-208 administration. ODM-208 was well tolerated with steroid hormone replacement. The toxicity findings were considered related to CYP11A1 inhibition and were reversed after stopping of the compound administration. Steroid hormone biosynthesis can be effectively inhibited with a small-molecule inhibitor of CYP11A1. The findings suggest that administration of ODM-208 is feasible with concomitant corticosteroid replacement therapy.

The Immunobiogram, a novel in vitro diagnostic test to measure the pharmacodynamic response to immunosuppressive therapy in kidney transplant patients

BackgroundDiagnostic tools to measure the response to individual immunosuppressive drugs for transplant patients are currently lacking. We previously developed the blood-based Immunobiogram bioassay for in-vitro characterization of the pharmacodynamic response of patients' own immune cells to a range of immunosuppressants. We used Immunobiogram to examine the association between patients' sensitivity to their prescribed immunosuppressants and clinical outcome. MethodsWe conducted an international, multicenter, observational study in a kidney transplant population undergoing maintenance immunosuppressive therapy. Patients were selected by clinical course poor [PCC] N = 53 (with renal dysfunction, and rejection signs in biopsy or/and an increase in DSA strength in last 12 months) versus good [GCC] N = 50 (with stable renal function and treatment, no rejection and no DSA titers). Immunobiogram dose-response curve parameters were compared between both subgroups in patients treated with mycophenolate, tacrolimus, corticosteroids, cyclosporine A or everolimus. Parameters for which significant inter-group differences were observed were further analyzed by univariate and subsequent multivariate logistic regression. ResultsClinical outcome was associated with following parameters: area over the curve (AOC) and 25% (ID25) and 50% (ID50) inhibitory response in mycophenolate, tacrolimus, and corticosteroid-treated subgroups, respectively. These statistically significant associations persisted in mycophenolate (OR 0.003, CI95% <0.001–0.258; p = 0.01) and tacrolimus (OR < 0.0001, CI95% <0.00001–0.202; p = 0.016) subgroups after adjusting for concomitant corticosteroid treatment, and in corticosteroid subgroup after adjusting for concomitant mycophenolate or tacrolimus treatment (OR 0.003; CI95% <0.0001–0.499; p = 0.026). ConclusionsOur results highlight the potential of Immunobiogram as a tool to test the pharmacodynamic response to individual immunosuppressive drugs.