Sustained Treatment Response Research Articles

Outcomes of Down-Titration in Patients with Severe Scalp Alopecia Areata Initially Treated with Baricitinib 4-mg: Week 152 data from BRAVE-AA2

BackgroundBaricitinib, an oral selective Janus kinase inhibitor, is approved to treat adults with severe alopecia areata (AA). ObjectiveTo report the Week 152 efficacy results from the Phase 3 trial BRAVE-AA2 down-titration sub-study. MethodsBRAVE-AA2 enrolled 546 adults with severe AA (Severity of Alopecia Tool [SALT] score ≥50). Baricitinib 4-mg treated patients achieving a clinical response (SALT score ≤20) at Week 52 were rerandomized 1:1 to stay on 4-mg or down-titrate to 2-mg. Last observation carried forward was used to impute missing or censored data. ResultsAt Week 52, 86/234 (36.8%) baricitinib 4-mg treated patients were eligible for down-titration; 44 remained on 4-mg while 42 down-titrated to 2-mg. At Week 152, 39/44 (88.6%) 4-mg treated patients had maintained clinical response, compared to 24/41 (58.5%) down-titrated patients. Among down-titrated patients, loss of treatment benefit was less frequent in those with sustained response and SALT score ≤5 at Week 52. LimitationsMethod and timing of down-titration were pre-specified in the protocol based on Week 52 responder status and not on other clinical factors. ConclusionMore than half of down-titrated patients maintained response. Sustained treatment response and/or near-total regrowth may be associated with a greater likelihood of response maintenance after down-titration.

Efficacy and safety of self-expandable metallic stents for management of benign gastric outlet obstruction-A prospective study.

We aimed at evaluating the safety and efficacy of self-expandable metallic stent (SEMS) insertion for managing patients with benign gastric outlet obstruction (GOO). This prospective interventional study included 23 patients. All consecutive treatment-naïve symptomatic patients with benign GOO were recruited. Fully covered SEMS were deployed across the stricture under fluoroscopic and endoscopic guidance. Technical success, clinical success and sustained treatment response (STR) were assessed. Technical success was defined as the successful deployment of SEMS at the desired anatomic location. Clinical success was defined as the resolution of symptoms and an increase in Gastric Outlet Obstruction Scoring System (GOOSS) of at least 1 point from the baseline score on Day 7. STR was assessed at four and eightweeks post stent removal in patients who had a response at week four. Factors associated with stent migration and non-response at week four were also assessed. The median age of the study population was 30years (range 19-65years). Males constituted 65.22%. Most patients presented with vomiting (100%) and abdominal pain (95.65%). Peptic stricture was most common etiology for GOO (60.9%) followed by tubercular (26.1%) and corrosive (13%). Most common site of obstruction was junction of first and second part of duodenum (69.57%) followed by pyloric (30.43%). Median length of stricture was 2cm (range 1.5-4). Technical success was achieved in all 23 patients (100%). Clinical success was achieved in 21 patients (91.3%). Response at Day 28 was seen in 20 patients (86.95%). Eighteen of 20 (90%) patients who had a response at week four had STR at week four and week eight after stent removal. Stent migration occurred in five (21.7%) patients. On univariate analysis, stricture length, calibre and stent length were found to predict migration. Fully covered SEMS was an effective and safe management modality in patients with benign GOO. Stent migration remains a troublesome disadvantage.

Sustained benefits of onabotulinumtoxinA treatment in chronic migraine: An analysis of the pooled Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) randomized controlled trials.

To characterize the long-term (56-week) benefits of continuous onabotulinumtoxinA treatment response in individuals with chronic migraine (CM) who achieved reduction to <15 headache days/month with treatment. There are limited data exploring reductions in monthly headache days to levels consistent with episodic migraine among those experiencing CM. Understanding the impact of sustained preventive treatment response in CM can provide important information about the impact of successful therapy. The two Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy trials of onabotulinumtoxinA in adults included a 24-week, randomized, double-blind, placebo-controlled phase and a 32-week open-label phase. Data were pooled to determine proportions of individuals with <15 headache days/month while on treatment during several time periods in the double-blind phase (Weeks 21-24; any 12 consecutive weeks; Weeks 13-24) and the entire study (Weeks 53-56; any 12 consecutive weeks; any 4-week period). We assessed the long-term impact on mean monthly headache days and changes from baseline on the six-item Headache Impact Test (HIT-6) and Migraine-Specific Quality of Life questionnaire version 2.1 (MSQv2.1). We analyzed 1384 participants with chronic migraine (double-blind: onabotulinumtoxinA, n = 688; placebo, n = 696; open-label: n = 688 [onabotulinumtoxinA]). The discontinuation rates prior to the completion of the full 56-week treatment period for onabotulinumtoxinA and placebo were 25.4% (n = 175) and 29.3% (n = 204), respectively. During Weeks 13-24 of the double-blind phase, significantly more onabotulinumtoxinA-treated (386/688 [56.1%]) than placebo-treated (342/696 [49.1%]) individuals had <15 headache days/month (p = 0.010), with fewer monthly headache days for onabotulinumtoxinA versus placebo responders. The proportions of participants achieving <15 monthly headache days with onabotulinumtoxinA were 60.9% (419/688) at Weeks 25-56, 81.1% (558/688) at Weeks 53-56, and 79.4% (546/688) during any consecutive 12-week period. Mean changes from baseline on the HIT-6 and MSQv2.1 questionnaire surpassed within-group minimal important difference thresholds in all periods. At Week 24, onabotulinumtoxinA-treated participants who achieved <15 monthly headache days during Weeks 21-24 had a greater mean HIT-6 score reduction (-6.5 vs. -1.4) and greater mean MSQv2.1 Role-Function Restrictive score improvements (21.3 vs. 6.4) than those who did not achieve <15 monthly headache days during the same period. Participants who achieved <15 monthly headache days with onabotulinumtoxinA treatment achieved meaningful benefits in headache-related disability and migraine-specific quality of life compared with those who remained at or above the 15-monthly headache days threshold. Sustained benefits observed over 56 weeks support long-term onabotulinumtoxinA use for the prevention of CM.

Toxicity-Induced Discontinuation of Immune Checkpoint Inhibitors in Metastatic Urothelial Cancer: 6-Year Experience from a Specialized Uro-Oncology Center.

Immune checkpoint inhibitor (ICI) therapies have been established as the standard-of-care in various uro-oncological cancers. Immune-related adverse events (irAEs) are frequent, but their degree rarely leads to the discontinuation of immunotherapies. Unplanned permanent treatment discontinuation may negatively impact the outcomes of patients, but there are emerging data about a positive correlation between emergence of severe irAEs and therapeutic cancer responses. In this study, a retrospective analysis of patients treated for urothelial carcinoma (UC) with ICI-based immunotherapy was conducted. irAEs were classified according to the Common Terminology Criteria for Adverse Events (CTCAEs) and radiological responses according to the Response Evaluation Criteria In Solid Tumors (RECISTs). Out of 108 patients with metastatic urothelial cancer that underwent immunotherapy, 11 experienced a severe irAE that required permanent discontinuation of ICI therapy. The most frequent irAEs leading to discontinuation were hepatitis (n = 4), pneumonitis (n = 2), and gastritis or colitis (n = 2). Prior to discontinuation (R1), the radiological best response was complete remission (CR) in three patients, partial response (PR) in six, and stable disease (SD) in wo patients. After the discontinuation of ICI therapy (R2), the best responses were CR in six, PR in three, and SD in two patients. Following discontinuation, the majority of these patients showed a sustained treatment response, despite not receiving any cancer-specific treatment. The median time of response after discontinuation of ICI therapy was 26.0 (5.2-55.8) months. We propose accurate counseling and close follow-ups of patients following their discontinuation of ICI therapy due to irAEs, as responses can be durable and deep, and many patients do not require immediate subsequent therapies, even in urothelial cancer. More data are required to find predictors of the length of response to appropriately counsel patients.

EPS7.04 Sinus MRI demonstrates sustained treatment response in children after elexacaftor/tezacaftor/ivacaftor (E/T/I) therapy of a similar magnitude to oxygen-enhanced (OE-) lung MRI

EPS7.04 Sinus MRI demonstrates sustained treatment response in children after elexacaftor/tezacaftor/ivacaftor (E/T/I) therapy of a similar magnitude to oxygen-enhanced (OE-) lung MRI

Sustained Treatment Response and Global Improvements With Long-term Valbenazine in Patients With Tardive Dyskinesia.

Using data from KINECT® 4, a phase 3, 48-week study of valbenazine, post hoc analyses were conducted to assess long-term outcomes that are relevant to the real-world management of tardive dyskinesia (TD). Post hoc analyses of the participants of the KINECT 4 study who completed 48 weeks of open-label valbenazine (40 or 80 mg) treatment were conducted. Valbenazine effects on TD were evaluated using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change-TD (CGI-TD), and Patient Global Impression of Change (PGIC). Of 103 participants completing 48 weeks of treatment, 55% experienced clinically meaningful improvement (defined as ≥2-point reduction in AIMS total score [sum of items 1 - 7, evaluated by site raters]) by week 4; at week 48, 97% met this threshold. The percentage of completers who achieved AIMS total score response thresholds of ≥10% to ≥90% increased over time, with 86% of completers reaching ≥50% improvement. Of the 40 (39%) completers with AIMS ≥50% response at week 8, 38 (95%) sustained this response at week 48; 81% of those who did not meet this threshold at week 8 had achieved it by week 48. At week 48, more than 85% of completers achieved CGI-TD and PGIC ratings of "much improved" or "very much improved." The majority of participants who completed 48 weeks of treatment with once-daily valbenazine experienced substantial clinically meaningful and sustained TD improvements. These findings indicate that valbenazine can be a highly effective long-term treatment in patients with TD.

Challenges and proposed solutions to conducting Alzheimer's disease psychosis trials.

Alzheimer's disease psychosis (ADP) produces a significant burden for patients and their care partners, but at present there are no approved treatments for ADP. The lack of approved treatments may be due to the challenges of conducting clinical trials for this disease. This perspective article discusses distinct challenges and proposed solutions of conducting ADP trials involving seven key areas: (1) methods to reduce the variable and sometimes high rates of placebo response that occur for treatments of neuropsychiatric symptoms; (2) the use of combined or updated criteria that provide a precise, consensus definition of ADP; (3) the use of eligibility criteria to help recruit individuals representative of the larger ADP population and overcome the difficulty of recruiting patients with moderate-to-severe ADP; (4) consideration of multiple perspectives and implementation of technology to reduce the variability in the administration and scoring of neuropsychiatric symptom assessments; (5) the use of clinically appropriate, a priori-defined severity thresholds and responder cutoffs; (6) the use of statistical approaches that address absolute effect sizes and a three-tier approach to address the fluctuation of neuropsychiatric symptoms; and (7) the implementation of feasible diagnostic and target-engagement biomarkers as they become available. The goal of these proposed solutions is to improve the evaluation of potential ADP therapies, within the context of randomized, placebo-controlled trials with clinically meaningful endpoints and sustained treatment responses.

The C1q and gC1qR axis as a novel checkpoint inhibitor in cancer.

Understanding at the molecular level of the cell biology of tumors has led to significant treatment advances in the past. Despite such advances however, development of therapy resistance and tumor recurrence are still unresolved major challenges. This therefore underscores the need to identify novel tumor targets and develop corresponding therapies to supplement existing biologic and cytotoxic approaches so that a deeper and more sustained treatment responses could be achieved. The complement system is emerging as a potential novel target for cancer therapy. Data accumulated to date show that complement proteins, and in particular C1q and its receptors cC1qR/CR and gC1qR/p33/HABP1, are overexpressed in most cancer cells and together are involved not only in shaping the inflammatory tumor microenvironment, but also in the regulation of angiogenesis, metastasis, and cell proliferation. In addition to the soluble form of C1q that is found in plasma, the C1q molecule is also found anchored on the cell membrane of monocytes, macrophages, dendritic cells, and cancer cells, via a 22aa long leader peptide found only in the A-chain. This orientation leaves its 6 globular heads exposed outwardly and thus available for high affinity binding to a wide range of molecular ligands that enhance tumor cell survival, migration, and proliferation. Similarly, the gC1qR molecule is not only overexpressed in most cancer types but is also released into the microenvironment where it has been shown to be associated with cancer cell proliferation and metastasis by activation of the complement and kinin systems. Co-culture of either T cells or cancer cells with purified C1q or anti-gC1qR has been shown to induce an anti-proliferative response. It is therefore postulated that in the tumor microenvironment, the interaction between C1q expressing cancer cells and gC1qR bearing cytotoxic T cells results in T cell suppression in a manner akin to the PD-L1 and PD-1 interaction.

Use of hydroxocobalamin to treat intraoperative vasoplegic syndrome refractory to vasopressors and methylene blue during liver transplantation.

For patients with catecholamine-resistant vasoplegic syndrome (VS) during liver transplantation (LT), treatment with methylene blue (MB) and/or hydroxocobalamin (B12) has been an acceptable therapy. However, data on the effectiveness of B12 is limited to case reports and case series. We retrospectively reviewed records of patients undergoing LT from January 2016 through March 2022. We identified patients with VS treated with vasopressors and MB, and abstracted hemodynamic parameters, vasopressor requirements, and B12 administration from the records. The primary aim was to describe the treatment efficacy of B12 for VS refractory to vasopressors and MB, measured as no vasopressor requirement at the conclusion of the surgery. One hundred one patients received intraoperative VS treatment. For the 35 (34.7%) patients with successful VS treatment, 14 received MB only and 21 received both MB and B12. Of the 21 patients with VS resolution after receiving both MB and B12, 17 (89.5%) showed immediate, but transient, hemodynamic improvements at the time of MB administration and later showed sustained response to B12. Immediate but transient hemodynamic response to MB in VS patients during LT supports the diagnosis of VS and should prompt B12 administration for sustained treatment response.

Associations between adverse childhood experiences and history of weight cycling.

Adverse childhood experiences (ACEs) predict obesity onset; however, the relationship between ACEs and history of weight cycling has not been adequately explored. This gap is problematic given the difficulty in weight loss maintenance and the impact of ACEs on obesity development, chronicity, and associated weight stigma. The objective of this study was to examine associations between self-reported history of ACEs and weight cycling in a sample of weight loss treatment-seeking adults with overweight/obesity. The number of participants in the analyzed sample was 78, mostly white educated adult women (80% female, 81% Caucasian, 75%≥bachelor's degree) with excess adiposity enrolled in the Cognitive and Self-regulatory Mechanisms of Obesity Study. ACEs were measured at baseline using the ACEs Scale. History of weight cycling was measured using the Weight and Lifestyle Inventory that documented weight loss(es) of 10 or more pounds. Higher ACE scores were associated with a greater likelihood of reporting a history of weight cycling. Participants with four or more ACEs had 8 times higher odds (OR=8.301, 95% CI=2.271-54.209, p=0.027) of reporting weight cycling compared with participants with no ACEs. The association of weight cycling for those who endorsed one to three ACEs was not significant (OR=2.3, 95% CI=0.771-6.857, p=0.135) in this sample. The role of ACEs in health may be related to associations with weight cycling. Results indicated that those who reported four or more ACEs had significantly higher odds of reporting weight cycling compared with those with no ACEs. Further research is needed to further explore how ACEs predict the likelihood of weight cycling, which may be prognostic for sustained weight loss treatment response and weight stigma impacts.

Mechanisms of action underlying virtual reality exposure treatment in spider phobia: Pivotal role of within-session fear reduction

Although virtual-reality exposure treatment (VRET) for anxiety disorders is an efficient treatment option for specific phobia, mechanisms of action for immediate and sustained treatment response need to be elucidated. Towards this aim, core therapy process variables were assessed as predictors for short- and long-term VR treatment outcomes. In a bi-centric study, n = 186 patients with spider phobia completed a baseline-assessment, a one-session VRET, a post-therapy assessment, and a 6-month-follow-up assessment (ClinicalTrials.gov, ID: NCT03208400). Short- and long-term outcomes regarding self-reported symptoms in the spider phobia questionnaire (SPQ) and final patient-spider distance in the behavioral avoidance test (BAT) were predicted via logistic regression models with the corresponding baseline score, age, initial fear activation, within-session fear reduction and fear expectancy violation as predictors. To predict long-term remission status at 6-month-follow-up, dimensional short-term changes in the SPQ and BAT were additionally included. Higher within-session fear reductions predicted better treatment outcomes (long-term SPQ; short- and long-term BAT). Lower initial fear activation tended to be associated with better long-term outcomes (SPQ), while fear expectancy violation was not associated with any outcome measure. Short-term change in the SPQ predicted remission status. Findings highlight that in VRET for spider phobia, the experience of fear reduction is central for short- and long-term treatment success and should be focused by therapists.

The Response of Synthetic Adrenocorticotropic Hormone (ACTH) Treatment in Pediatric Drug-Resistant Epilepsy Other Than Infantile Epileptic Spasms Syndrome: A Retrospective Observational Study.

Adrenocorticotropic hormone (ACTH) is a tropic hormone naturally secreted by the anterior pituitary gland to stimulate the secretion of cortisol and androgens.ACTH is used innon-tuberous sclerosis infantile epileptic spasms syndrome (IESS), and ithas shown significant, promising results in epilepsy syndromes with possible inflammatory processes.However, many studies have also demonstrated a promising potential even in other types of drug-resistant epilepsy. Material and method: This study is a retrospective observational study that follows the clinical characteristics and outcomes of nine pediatric patients with drug-resistant epilepsy treated with short-term synthetic ACTH in Saudi Arabia. The response was assessed during the ACTH infusion and after three months. During infusion, six of the nine (66%) patients had a short-term (within two weeks) favorable response, with a more than 50% reduction in seizure frequency. Four of the nine (44%) patients had complete responses with seizure freedom. After three months, four patients (44%) had a three-month seizure frequency reduction of more than 30% attributed to ACTH, including one patient with an IESS history who had a 70% reduction in seizure frequency. Of the four patients who had a complete response, three (75%) had a seizure relapse after tapering in the following three months. Conclusion: This case series adds to the literature to suggest ACTH treatment of drug-resistant epilepsies other than IESS might benefit some patients in the acute settingbut they are less likely to maintain a sustained treatment response. Randomized and large sample size studies are necessary to assess treatment response and accurately aid in appropriate patient selection.

Stratum Corneum Hydration As a Potential Marker of Response to Dupilumab in Atopic Dermatitis®: A Prospective Observational Study.

Background: Dupilumab is an effective treatment for atopic Dermatitis® (AD) and it also restores skin barrier function. Nevertheless, early changes in epidermal barrier parameters related to sustained treatment response or treatment failure are not known. So, the objective of this study is to evaluate whether changes in skin barrier function after 16 weeks dupilumab treatment could predict sustained treatment response or treatment failure. Materials and Methods: A prospective observational study was conducted that included patients with AD starting dupilumab. Clinical scores, patient-reported outcome measures (PROMs), and skin barrier function parameters were assessed at baseline and after 16 weeks treatment. Patients were followed until they failed to dupilumab or until the end of the study period. Participants were divided into 2 groups: patients with treatment failure and those with sustained treatment response. Results: In total, 32 patients with AD were included in the study, with a mean age of 28.03 years (standard deviation 10.65), being 20 (60.6%) females. In total, 22 (66.7%) patients sustained dupilumab response during the study period and only 10 (33.3%) failed to treatment. After 16 weeks treatment, clinical scores were improved in both groups. Patients with sustained treatment response increased stratum corneum hydration (SCH) on noninvolved skin (34.25 arbitrary units [AU] vs 44.90AU, P = 0.001) and on eczematous lesions (20.71 AU vs 40.94 AU, P < 0.001) and also decreased transepidermal water loss (TEWL) on eczematous lesions (28.22 g/[m2·h] vs 14.83 g/[m2·h], P = 0.002). Patients with treatment failure did not change TEWL or SCH. SCH after 16 weeks treatment on noninvolved skin (odds ratio [OR] = 0.83, P = 0.018) and SCH after 16 weeks treatment on eczematous lesions (OR = 0.86, P = 0.028) were related to dupilumab failure. Conclusion: SCH could be used as a predictive biomarker of dupilumab response in patients with AD.

Prospective >12 Months Outcomes After Vocal Fold Injection Medialization With Silk Microparticle-Hyaluronic Acid Material.

Vocal fold injection medialization (VFIM) is widely used as an initial treatment for unilateral vocal fold paralysis (UVFP). Current practices employ materials that share the limitation of temporary clinical effect from variable resorption rates. A novel silk protein microparticle-hyaluronic acid-based material (silk-HA) has demonstrated cellular infiltration and tissue deposition that may portend a durable medialization effect. We report on ≥12 months outcomes after VFIM with silk-HA. Prospective open-label study of patients with UVFP that elected treatment with VFIM with silk-HA. Blinded experts rated laryngeal stroboscopic exams. Seventeen patients with UVFP underwent VFIM with silk-HA. Twelve of the 17 patients have ≥12 months follow-up. Seven patients demonstrated durable treatment benefit ≥12 months after injection with median improvement of 19 (p = 0.0156) in VHI-10. There was no significant change in VHI-10 between 1 and 12 months for these patients. Blinded ratings indicated that 5/7 patients with sustained improvements in VHI-10 exhibited complete or touch glottal closure at 12 months. Two of the seven patients exhibited a small (<1 mm) glottal gap at 12 months. Seven patients experienced initial benefit with later regression 3-4 months after injection. VFIM with silk-HA can offer durable improvement in voice-related outcomes for UVFP past 12 months. A subset of patients treated with silk-HA experienced early loss of effect around 3-4 months postinjection. Clinical factors predictive of sustained treatment response to silk-HA injection require further exploration. 3 Laryngoscope, 134:3679-3685, 2024.

Psilocybin therapy: A novel approach to treating depression

Psilocybin therapy: A novel approach to treating depression

Extended Exposure Topotecan Significantly Improves Long-Term Drug Sensitivity by Decreasing Malignant Cell Heterogeneity and by Preventing Epithelial-Mesenchymal Transition.

Maximum tolerable dosing (MTD) of chemotherapeutics has long been the gold standard for aggressive malignancies. Recently, alternative dosing strategies have gained traction for their improved toxicity profiles and unique mechanisms of action, such as inhibition of angiogenesis and stimulation of immunity. In this article, we investigated whether extended exposure (EE) topotecan could improve long-term drug sensitivity by preventing drug resistance. To achieve significantly longer exposure times, we used a spheroidal model system of castration-resistant prostate cancer. We also used state-of-the-art transcriptomic analysis to further elucidate any underlying phenotypic changes that occurred in the malignant population following each treatment. We determined that EE topotecan had a much higher barrier to resistance relative to MTD topotecan and was able to maintain consistent efficacy throughout the study period (EE IC50 of 54.4 nM (Week 6) vs. MTD IC50 of 2200 nM (Week 6) vs. 83.8 nM IC50 for control (Week 6) vs. 37.8 nM IC50 for control (Week 0)). As a possible explanation for these results, we determined that MTD topotecan stimulated epithelial-mesenchymal transition (EMT), upregulated efflux pumps, and produced altered topoisomerases relative to EE topotecan. Overall, EE topotecan resulted in a more sustained treatment response and maintained a less aggressive malignant phenotype relative to MTD topotecan.

Sustained Treatment Response with Long-Term Valbenazine in Patients with Tardive Dyskinesia (P11-11.012)

Sustained Treatment Response with Long-Term Valbenazine in Patients with Tardive Dyskinesia (P11-11.012)

Typical disease courses of patients with unipolar depressive disorder after in-patient treatments-results of a cluster analysis of the INDDEP project.

Previously established categories for the classification of disease courses of unipolar depressive disorder (relapse, remission, recovery, recurrence) are helpful, but insufficient in describing the naturalistic disease courses over time. The intention of the present study was to identify frequent disease courses of depression by means of a cluster analysis. For the longitudinal cluster analysis, 555 datasets of patients who participated in the INDDEP (INpatient and Day clinic treatment of DEPression) study, were used. The present study uses data of patients with at least moderate depressive symptoms (major depression) over a follow-up period of 1 year after their in-patient or day-care treatments using the LIFE (Longitudinal Interval Follow-Up Evaluation)-interview. Eight German psychosomatic hospitals participated in this naturalistic observational study. Considering only the Calinski-Harabatz index, a 2-cluster solution gives the best statistical results. In combination with other indices and clinical interpretations, the 5-cluster solution seems to be the most interesting. The cluster sizes are large enough and numerically balanced. The KML-cluster analyses revealed five well interpretable disease course clusters over the follow-up period: "sustained treatment response" (N = 202, 36.4% of the patients), "recurrence" (N = 80, 14.4%), "persisting relapse" (N = 115, 20.7%), "temporary relapse" (N = 95, 17.1%), and remission (N = 63, 11.4%). The disease courses of many patients diagnosed with a unipolar depression do not match with the historically developed categories such as relapse, remission, and recovery. Given this context, the introduction of disease course trajectories seems helpful. These findings may promote the implementation of new therapy options, adapted to the disease courses.

Sustained Treatment Response With Long-Term Valbenazine in Patients With Tardive Dyskinesia

AbstractBackgroundValbenazine is a once-daily VMAT2 inhibitor approved for the treatment of tardive dyskinesia (TD), a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotics, antiemetics, and other dopamine receptor blocking agents. The efficacy, safety, and tolerability of valbenazine has been established in several phase 3 trials, including a long-term study (KINECT 4 [NCT02405091]) in which participants received open-label valbenazine (40 or 80 mg) for 48 weeks. Post hoc analyses of KINECT 4 data were conducted to assess patterns of treatment response.MethodsData from KINECT 4 treatment completers (participants who reached the Week 48 visit and had the longest duration of treatment) were analyzed post hoc. TD was assessed using the Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1–7, as rated by the study investigator), the Clinical Global Impression of Change-Tardive Dyskinesia (CGI-TD), and the Patient Global Impression of Change (PGIC). Analyses were conducted at Week 8 (first study visit after the valbenazine dose-optimization period) and Week 48 using the following definitions of response: ≥50% and ≥70% improvement from baseline in AIMS total score; rating of “much improved” or “very much improved” (score ≤2) on the CGI-TD and PGIC.ResultsOf the 167 participants who entered KINECT 4, 103 (62%) were treatment completers and included for analysis. Of these 103 participants, 39% and 86% met the ≥50% AIMS response threshold at Weeks 8 and 48, respectively. The percentages of participants who met the highly rigorous AIMS ≥70% response threshold at Weeks 8 and 48 were 17% and 52%, respectively. Of the 40 participants with AIMS ≥50% total score improvement at Week 8, 95% also met this threshold at Week 48 (“sustained response”). Of the 63 participants with &lt;50% AIMS improvement at Week 8, 81% achieved the ≥50% response threshold by end of treatment at Week 48. The proportion of participants meeting the threshold for CGI-TD response also increased over time, from 50% at Week 8 to 92% at Week 48. PGIC results were similar, with response rates of 53% and 88% at Weeks 8 and 48, respectively.ConclusionsPost hoc analyses of data from a 48-week, open-label study of once-daily valbenazine showed that the proportion of participants meeting rigorous treatment response thresholds increased over time. By the end of treatment at Week 48, &gt;80% of participants demonstrated robust improvements in TD, as assessed using the AIMS (≥50% improvement), CGI-TD (score ≤2), and PGIC (score ≤2).FundingNeurocrine Biosciences, Inc.

P701 A time-to-event model relating infliximab trough concentrations to the risk of relapse after extending the infusion interval

Abstract Background Extending the infliximab infusion interval has been attempted in patients with Crohn’s disease (CD) and ulcerative colitis (UC) who sustained treatment response following an earlier interval shortening. We aimed to identify predictors of sustained remission after infliximab interval extension. Methods: Data from 30 adult patients (17 CD, 13 UC), who underwent infliximab interval extension following earlier interval shortening, were collected from a single-centre database search. All patients were in steroid-free clinical (two-item patient-reported outcome [PRO2] ≤1 [UC] and ≤8 [CD]) and biological (C-reactive protein [CRP] &amp;lt;5 mg/L or faecal calprotectin [FC] &amp;lt;250 mg/kg) remission at interval extension. Time-to-relapse was modelled using a time-to-event (TTE) model with loss of steroid-free clinical and biological remission being the event of interest (NONMEM7.5). Various hazard functions were explored, and disease type, time-varying infliximab concentrations and infliximab clearance were investigated as predictors of the relapse hazard risk. The infliximab clearance was calculated using weighted averaging of the estimates of 18 population pharmacokinetics models.1 Results In total, 37% of patients (n=11) remained relapse-free until one year after infliximab interval extension (Figure 1). A time-constant (exponential) hazard model proved best to describe the relapse data of patients with CD (Figure 2, Table 1). The Gompertz hazard model best described the data of patients with UC, with the relapse hazard risk increasing over time. Patients with CD had an overall higher relapse hazard risk than patients with UC. For patients with UC, the infliximab trough concentration was negatively related to the relapse hazard risk and was included in the model using a sigmoidal inhibitory Emax function. Also, in patients with UC, a higher infliximab clearance was associated with an increase in the relapse risk. The infliximab clearance was also a predictor of the relapse hazard risk, but its effect could not be precisely estimated. Conclusion Patients with CD had a higher relapse risk than patients with UC. Only in patients with UC, the hazard risk increased with time, but this risk was lower when the infliximab trough concentration increased. No exposure-response relationship was observed in patients with CD. Results of this exploratory analysis should be interpreted with care and prospective confirmation is awaited (MODIFI study; NCT04982172).2 1Kantasiripitak W. et al. CPT PSP. 2022 2Sheiner LB. et al. CPT. 1997