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Abstract Background Ulcerative colitis (UC) has a detrimental impact on patients’ health-related quality of life (HRQoL).1 Long-term treatment goals for patients with moderately to severely active UC include restoration of HRQoL. This post-hoc analysis evaluated the effect of induction and maintenance treatment with risankizumab (RZB) on HRQoL outcomes. Methods Data from two Phase 2b/3 clinical trials (INSPIRE induction: NCT03398148 and COMMAND maintenance: NCT03398135) were evaluated. Patients received RZB 1200 mg intravenous (IV) or placebo (PBO) induction treatment at weeks 0, 4, and 8. Patients with a clinical response per Adapted Mayo score to RZB IV were randomised 1:1:1 to subcutaneous (SC) RZB 180 or 360 mg, or placebo (PBO [RZB withdrawal] SC) every 8 weeks for 52 weeks of maintenance. The proportion of patients achieving a meaningful within-person change (MWPC) for each HRQoL outcome was reported. HRQoL outcomes included Functional Assessment of Chronic Illness Therapy-Fatigue, disease-specific instruments such as Inflammatory Bowel Disease Questionnaire (IBDQ) and Ulcerative Colitis Symptom Questionnaire (UCSQ), as well as generic quality-of-life questionnaires like Work Productivity and Activity Index-Ulcerative Colitis (WPAI-UC), 36-Item Short-Form Survey (SF-36), and EuroQoL 5 Dimensions 5 Levels. MWPCs were measured from baseline to induction Week 12 and to maintenance Week 52. Estimated differences in proportions with 95% confidence intervals and p-values between RZB and PBO were compared using the Cochran-Mantel-Haenszel test adjusting for baseline strata. Results For RZB 1200 mg IV (n=650) versus PBO IV-treated (n=325) patients, a greater proportion of patients achieved MWPC across all HRQoL outcomes at Week 12 of induction (p<0.01; Table). At Week 52 of maintenance, a greater proportion of patients treated with RZB 180 mg SC (N=179) versus PBO (withdrawal) SC (N=183) achieved MWPC across all HRQoL outcomes (p<0.05), except for absenteeism from WPAI-UC (p=0.33). For RZB 360 mg SC (N=186) versus PBO (withdrawal) SC, a greater proportion of patients achieved MWPC for UCSQ, IBDQ, and SF-36 physical component summary (all p<0.05). Conclusion In this analysis, a greater proportion of patients treated with RZB versus PBO achieved MWPC on various HRQoL outcomes after completing 12-week induction IV therapy. HRQoL improvements were sustained up to Week 52 of treatment. This suggests RZB has the potential to help patients achieve restoration of HRQoL as a long-term goal of treatment in patients with moderately to severely active UC. 1. Mavroudis G. Therap Adv Gastroenterol. 2022;15:17562848211062406.

Abstract Background Darvadstrocel (DVS), a suspension of expanded allogeneic adipose-derived mesenchymal stem cells, is approved for the treatment of complex Crohn’s perianal fistulas (CPF). INSPIRE (EUPAS24267) is a European observational post-approval study evaluating real-world effectiveness and safety of DVS in patients with complex CPF for up to 36 months. Here we report preliminary clinical and safety outcomes from INSPIRE. Methods Patients with complex CPF who had received DVS according to local standard practice were eligible to enrol. Clinical response (closure of ≥50% of external openings [EOs]) and clinical remission (closure of all EOs) of DVS-treated fistulas that were draining at baseline, were evaluated in the all-treated (AT; received ≥1 dose of DVS with an evaluation for fistula response after 6 months) and per-protocol (PP; received DVS as per label-approved guidelines) cohorts. Treatment-emergent adverse events (TEAEs), serious TEAEs and AEs of special interest were reported for the safety cohort (all patients treated with DVS). Results As of April 2023, 652 patients had enrolled (Table 1). Complete data to evaluate 12-month clinical response and remission were available for 134 (AT cohort) and 124 (PP cohort) patients, of whom 79.9% (AT, n = 107) and 79.8% (PP, n = 99) had a clinical response and 76.1% (AT, n = 102) and 76.6% (PP, n = 95) had clinical remission (Figure 1). From baseline to Month 12, there was a decrease in the mean (standard deviation [SD]) Perianal Disease Activity Index score (–3.5 [3.3]; n/N = 96/302 and –3.7 [3.2]; n/N = 89/249) and a decrease in the mean (SD) Harvey–Bradshaw Index for Crohn’s disease activity (-0.3 [2.8]; n/N = 102/302 and -0.4 [2.9]; n/N = 95/249) in the AT and PP cohorts, respectively. Complete safety data were available for 619 patients (median [min–max] follow-up 480 [6–1595]) days. Overall, 26% (n = 162) had ≥1 TEAE and 10% (n = 63) ≥1 serious TEAE. The most frequent TEAEs were anal abscess (6.9%), COVID-19 (1.9%) and proctalgia (1.1%). No deaths were reported. One breast cancer lymph node metastasis and one ovarian epithelial cancer were reported; both events were confounded by immunosuppressant treatment and were not considered related to DVS treatment. Conclusion These preliminary data are consistent with the pivotal ADMIRE-CD study and demonstrate a single dose of DVS in patients with complex CPF is associated with positive clinical outcomes in up to 80% of patients, and a favourable safety profile, both of which are maintained after 12 months. The inherent limitations of registry-based studies mean these data should be interpreted with caution. However, the ongoing INSPIRE study will provide longer follow-up data to confirm these observations with respect to any study limitations.

Abstract Background Complex perianal fistulas are a serious complication in patients with Crohn’s disease (CD). Darvadstrocel (DVS), a suspension of expanded adult allogeneic adipose-derived mesenchymal stem cells, is approved in Europe and Japan for treatment of complex Crohn’s perianal fistulas (CPF). The global ADMIRE-CD II phase 3 randomized double-blind placebo-controlled study evaluated the efficacy and safety of DVS for treatment of complex CPF. Methods Patients aged 18–75 years with clinically controlled, inactive or mildly active CD and complex CPF (≤2 internal openings [IO] and ≤3 external openings [EOs]) who had an inadequate, or a loss of response to immunosuppressive agents or biologics were included. Patients were randomized 1:1 to receive a local injection of DVS as a single dose (120 x 106 cells/24 mL) or placebo. In all patients, fistula preconditioning included vigorous curettage and seton placement 2–3 weeks before treatment, and seton removal, a further curettage and closure of IOs immediately before treatment. The primary endpoint was combined remission (closure of all treated EOs that were draining at baseline, despite gentle finger compression, and absence of collections >2 cm confirmed by MRI) at 24 weeks. Secondary endpoints included combined remission at 52 weeks, clinical remission (closure of all treated EOs without MRI confirmation) at 24 and 52 weeks, and time to clinical remission at 24 weeks. Safety was monitored up to 52 weeks. Results From 19 Oct 2017 to 26 Jul 2023, 568 patients received DVS (n = 283) or placebo (n = 285) with fistula preconditioning; 56.3% of patients enrolled in Europe and Israel, and 43.7% in North America. Mean (SD) age, sex and race were similar in the DVS and placebo arms (38.4 [11.9] vs 37.7 [10.8] years; 42.8% vs 45.6% female; 85.9% vs 89.1% White). Combined remission rates at 24 weeks did not statistically differ between treatments (48.8% DVS vs 46.3% placebo) and there were no differences in secondary endpoints (Table 1; Figure 1). Based on health authority guidelines, post hoc analyses of patients randomized before COVID-19 (11 March 2020; n = 141 DVS, n = 143 placebo) were performed: combined remission rates at 24 weeks were 46.8% (DVS) and 38.5% (placebo). The safety profile for DVS was consistent with prior studies with no new safety signals (Table 1). Conclusion The efficacy outcomes assessed did not statistically differ between DVS and placebo, and the placebo response rate (with fistula preconditioning) was higher than expected. Post hoc analyses revealed lower placebo response rates in patients randomized before COVID-19 (similar to the pivotal ADMIRE CD I study) than the overall placebo arm. DVS was well tolerated.

TPS602 Background: Poorly differentiated neuroendocrine carcinoma (NEC) is an aggressive malignancy comprising both pulmonary and extrapulmonary primary sites. NEC includes both small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), as well as other neuroendocrine carcinomas arising from any primary organ. A substantial portion (~40%) of NEC arises from gastrointestinal primary sites. The optimal systemic therapy beyond first line platinum and etoposide is not established. There is a critical need to improve upon the median survival in the second line, as most patients do not survive more than 6 months. The efficacy of dual immune checkpoint inhibitor (ICIs) therapy in NEC shows some promise, but most tumors do not respond. One possible explanation for this is that the tumor microenvironment in NEC is non-inflamed. VSV-IFNβ-NIS is a vesicular stomatitis virus (VSV)-based oncolytic virus being tested in multiple early phase clinical trials. Preliminary studies of immune responses in patients receiving VSV-IFNβ-NIS therapy suggest some patients develop T cell responses to viral antigens and known tumor antigens. We hypothesize that VSV-IFNβ-NIS therapy may convert a non-inflamed or immune-excluded phenotype in NEC to a highly inflamed phenotype that sensitizes the tumor to ICIs. Methods: This is a phase 1-2 safety run-in study designed to determine the safety and efficacy of VSV-IFNβ-NIS in combination with dual ICI therapy, ipilimumab and nivolumab, followed by dose expansion in patients with refractory non-small cell lung cancer (NSCLC) or NEC. After a safety run-in, we will be testing the recommended phase 2 dose (RP2D) of VSV-IFNβ-NIS in an expansion cohort of patients with SCLC or NEC of any primary site. Patients must have previously progressed on at least one line of systemic therapy. Prior treatment with checkpoint inhibitors is permitted. Patients are treated with ipilimumab and nivolumab on day 1, followed by one RP2D of 1.0x10^11 TCID50 VSV-IFNβ-NIS on day 4, followed by nivolumab every 3 weeks and ipilimumab every 6 weeks until progression, up to 2 years. The primary objective is to estimate the response rate by RECIST 1.1. Secondary objectives include estimation of disease-control rate, duration or response, progression-free survival, overall survival, and safety signals. The NEC expansion cohort will seek to enroll 10 patients. If at least one objective response is observed, and safety is confirmed, the regimen will be considered for future study. Clinical trial information: NCT03647163 .

Key Points Drosophila can be a model for Dent Disease type 1. Drosophila Clc-C mutations function similar to human CLC-5 Dent 1 mutations. Background Drosophila serve as exceptional alternative models for in vivo and ex vivo research and may provide an avenue for in-depth investigation for human ClC-5 and Dent disease type 1 (DD1). The Drosophila ClC-c (CG5284) has sequence homology with human ClC-5 and is hypothesized to encompass similar functional and phenotypical roles with ClC-5 and variants that cause DD1. Methods Ion transport function and activity of Drosophila ClC-c and homologous DD1 variants were assessed by voltage clamp electrophysiology. Membrane localization was demonstrated in Drosophila expressing a GFP-labeled construct of ClC-c. Genetic expression of an RNAi against ClC-c mRNA was used to generate a knockdown fly that serves as a DD1 disease model. Tubule secretion of cations and protein were assessed, as well as the crystal formation in the Malpighian tubules. Results Voltage clamp experiments demonstrate that ClC-c is voltage-gated with Cl − -dependent and pH-sensitive currents. Inclusion of homologous DD1 mutations pathogenic variants (S393L, R494W, and Q777X) impairs ClC-c ion transport activity. In vivo expression of ClC-c-eGFP in Malpighian tubules reveals that the membrane transporter localizes to the apical membrane and nearby cytosolic regions. RNAi knockdown of ClC-c (48% decreased mRNA expression) causes increased secretion of both urinary protein and Ca 2+ and increased occurrence of spontaneous tubule crystals. Conclusions Drosophila ClC-c shows orthologous function and localization to human ClC-5. Thus, Drosophila and ClC-c regulation may be useful for future investigations of Cl − transport, Ca 2+ homeostasis, and urinary protein loss in DD1.

Abstract Refinement of breast cancer risk estimates with a polygenic-risk score (PRS) may improve uptake of risk-reducing endocrine therapy (ET). A previous clinical trial assessed the influence of adding a PRS to traditional risk estimates on ET use. We stratified participants according to PRS-refined breast cancer risk and evaluated ET use and ET-related quality of life (QOL) at 1-year (previously reported) and 2-year follow-ups. Of 151 participants, 58 (38.4%) initiated ET, and 22 (14.6%) discontinued ET by 2 years; 42 (27.8%) and 36 (23.8%) participants were using ET at 1- and 2-year follow-ups, respectively. At the 2-year follow-up, 39% of participants with a lifetime breast cancer risk of 40.1% to 100.0%, 18% with a 20.1% to 40.0% risk, and 16% with a 0.0% to 20.0% risk were taking ET (overall P = 0.01). Moreover, 40% of participants whose breast cancer risk increased by 10% or greater with addition of the PRS to a traditional breast cancer-risk model were taking ET versus 0% whose risk decreased by 10% or greater (P = 0.004). QOL was similar for participants taking or not taking ET at 1- and 2-year follow-ups, although most who discontinued ET did so because of adverse effects. However, these QOL results may have been skewed by the long interval between QOL surveys and lack of baseline QOL data. PRS-informed breast cancer prevention counseling has a lasting, but waning, effect over time. Additional follow-up studies are needed to address the effect of PRS on ET adherence, ET-related QOL, supplemental breast cancer screening, and other risk-reducing behaviors. Prevention Relevance: Risk-reducing medications for breast cancer are considerably underused. Informing women at risk with precise and individualized risk assessment tools may substantially affect the incidence of breast cancer. In our study, a risk assessment tool (IBIS-polygenic-risk score) yielded promising results, with 39% of women at highest risk starting preventive medication.

Abstract There are striking differences among caregivers of people with dementia (PWDs) in how their health and well-being changes during active caregiving; however, less is known about these differences after caregiving has ended. One important factor influencing caregiver health is the emotional quality of the caregiver-PWD relationship. The present study evaluated caregivers’ emotional connection to the PWD (during caregiving) and associations with caregivers’ depression both concurrently (N = 326 active caregivers) and longitudinally (n = 91 former caregivers). Active caregivers described a recent time they felt connected to the PWD, and their responses were transcribed verbatim. Caregivers’ emotional connection to the PWD was operationalized by summing the number of positive and negative emotion words from the transcripts using text analysis software and dividing each figure by the total number of words in the response. Results indicated that neither positive nor negative emotional language was significantly correlated with caregivers’ concurrent depression. However, two-wave latent change score modeling revealed that caregivers’ greater positive emotional language (adjusting for caregivers’ baseline depression and negative emotional language) predicted steeper declines in depression (i.e., improvements in depression trajectories) after the death of the PWD (ß = -.11, SE(ß) = 0.04, p = .033). Negative emotional language was not significantly associated with changes in caregivers’ depression. This finding highlights positive emotion expressed by caregivers when describing their connection with the PWD as a potential resilience factor and underscores the important role that positive emotional qualities of the caregiving relationship play in improving caregivers’ mental health after caregiving ends.

Abstract Lower income in familial caregivers has been shown to associate with increased distress, depression, and burden during active caregiving. However, findings are less clear on whether lower income associates with changes in well-being that occur after caregiving ends. To investigate this question further, we recruited familial caregivers (CGs) of people with neurodegenerative diseases (PWD; N=36). Emotional well-being was assessed using the SF-36 Emotional Well-being and Energy scales both during active caregiving and after caregiving had ended (predominantly due to the PWD’s death or transition to institutional care, ~10 years later). Household income was measured after active caregiving had ended. Overall, CG’s emotional well-being and energy improved between active caregiving and after caregiving had ended (emotional well-being change: t(35) = 2.22, p = .033; energy change: t(35) = 2.88, p = .007). However, this improvement associated with household income, such that when controlling for levels during active caregiving, income associated with worse emotional well-being (B = -6.72, t(33) = -4.56, p < .001) and energy (B = -8.07, t(33) = -4.99, p < .001) in caregivers after caregiving had ended. During the adjustment period after caregiving ends, lower income may limit opportunities for caregivers to take time away from work to mourn the loss of their loved one or address their own health concerns adequately. Thus, low-income caregivers may experience fewer of the benefits associated with these activities. These findings underscore the importance of providing support for lower income caregivers during the critical period after caregiving ends.