Open-label Long-term Extension Research Articles

Long-term Etanercept Response for Patients with Radiographic Axial Spondyloarthritis Based on Achievement of Early, Intermediate, or Late Responses During Index Studies.

Short-term placebo (PBO)- or active-controlled clinical studies have demonstrated that etanercept (ETN) is effective and well tolerated in patients with radiographic axial spondyloarthritis (r-axSpA) with long-term efficacy and safety continuing for up to 7years after treatment start. Short-term randomized controlled trials (RCTs) have shown the efficacy of ETN after 12-24weeks, with statistically significant improvements as early as week 2. This post hoc analysis investigated the timeframe (i.e., temporal responses) in which patients with r-axSpA achieved their first clinical response with ETN and how patients responded over a longer period according to different temporal responses in index studies. Data were analyzed from three phase 3/4 PBO- or sulfasalazine-controlled RCTs of ETN for the treatment of r-axSpA (index studies). Long-term open-label extension (OLE) studies assessed how patients responded over a longer period according to different temporal responses ("Early," "Intermediate," "Late," or "Non-response") in their corresponding index studies. Within each index study, patient responses differed significantly between ETN and control arms for achievement of Assessment in SpondyloArthritis international Society (ASAS) 20 and other measures of treatment response. In general, the proportion of responders in the OLE studies was high for those with "Early" and "Intermediate" responses as defined in the index studies. Despite patients being considered non-responders in the index studies, a large proportion achieved response on continued treatment in the OLE studies over the longer term, including through 48weeks. Response in the index studies was maintained in the long term, and continued treatment was warranted in a large proportion of patients despite initial non-response. Absence of an early response in index studies did not predict non-response over the long term, and early response to treatment was not always a predictor for later response. NCT00421915; NCT00247962; NCT00356356; NCT00421980; NCT00410046.

DOP53 Long-term Efficacy and Safety of Risankizumab in Patients With Moderate to Severe Crohn's Disease up to 3 Years of Treatment: Results From the FORTIFY Open-Label Long-term Extension

Abstract Background The ongoing FORTIFY maintenance open-label extension (OLE) substudy evaluates the long-term efficacy and safety of risankizumab (RZB), a p19 interleukin-23 inhibitor, for treatment of moderate to severe Crohn’s disease (CD). Here, we report 2-year results of FORTIFY OLE. Methods The FORTIFY (NCT03105102) OLE enrolled patients (pts) who completed 52-wks maintenance dosing in the FORTIFY substudies or RZB phase 2 OLE.1,2 All pts received 180 mg subcutaneous (SC) RZB every 8 wks (Q8w), starting at wk56, except for pts who had prior rescue therapy (single 1200mg intravenous [IV] RZB dose then 360mg SC Q8w) who continued 360mg SC Q8w in the OLE. Pts with inadequate response (increased symptoms plus objective marker of inflammation) during the OLE could receive rescue therapy as described above. Pooled data from both treatment groups (RZB 180 mg & 360 mg SC) were assessed. Clinical outcomes were evaluated every 24 wks (endpoint definitions in Figure footnote). Endoscopy was performed every 96 wks. Results are reported as observed. Efficacy data for pts receiving rescue therapy in the OLE were included up to rescue initiation. Safety was assessed through the cutoff date of 05MAR2023. As this trial is ongoing, most patients have not reached the wk152 study visit. Any treatment-emergent adverse events (TEAEs) reported on or after the first dose in the OLE were analysed. Results As of the cutoff date, 1147 pts entered the OLE, of which 203 (17.6%) pts received rescue therapy during the OLE. Clinical response and remission rates were generally maintained with RZB from wks 56 to 152 (CD activity index [CDAI] clinical response, 85.8% to 86.5%, respectively; enhanced clinical response, 88.6% to 89.2%; CDAI clinical remission, 68.5% to 77.6%; stool frequency/abdominal pain score clinical remission, 64.4% to 71.0%) (Figure). At wks 56 and 152, respectively, rates of endoscopic response were 53.4% and 74.2%, endoscopic remission were 37.5%, and 58.9%, and ulcer-free endoscopy were 31.0% and 50.0%. There were no new trends for exposure-adjusted rates of TEAEs, and rates of adjudicated major cardiovascular adverse events, malignancies, serious infections and hepatic events remained stable with no new safety risks identified. There were no events of active tuberculosis, serious hypersensitivity, or adjudicated anaphylactic reaction. Three deaths occurred during the OLE (see Table footnote), all assessed by investigators as unrelated to study drug. Conclusion Pts receiving long-term RZB maintenance therapy in FORTIFY demonstrated sustained clinical and endoscopic efficacy with at least 3 years of treatment. The safety profile is consistent and supports long-term RZB treatment. 1doi: 10.1093/ecco-jcc/jjab093 2doi: 10.1016/S0140-6736(22)00466-4.

Short-term risk and long-term incidence rate of infection and malignancy with IL-17 and IL-23 inhibitors in adult patients with psoriasis and psoriatic arthritis: a systematic review and meta-analysis.

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022363127.

Mitapivat Treatment Reduces Levels of Interference in Work/School Activity for Adult Patients with Pyruvate Kinase Deficiency

Background: Pyruvate kinase (PK) deficiency is a rare hereditary disease resulting in chronic hemolytic anemia. It is associated with a range of acute and long-term complications and negatively impacts health-related quality of life. Patients (pts) with PK deficiency report daily social and physical limitations, which negatively impact various aspects of their lives, including the ability to perform at their full potential at work or school. Mitapivat is a first-in-class, oral, allosteric activator of PK, approved by the United States Food and Drug Administration for the treatment of hemolytic anemia in adults with PK deficiency, and by the European Union European Medicines Agency and the Medicines and Healthcare products Regulatory Agency in Great Britain for the treatment of PK deficiency in adults. Mitapivat has shown sustained and clinically meaningful improvements in the disease impact of PK deficiency measured by two disease-specific patient-reported outcome (PRO) instruments, the PK Deficiency Impact Assessment (PKDIA) and the PK Deficiency Diary (PKDD), in the pivotal ACTIVATE trial (NCT03548220) and its long-term extension (LTE) study (NCT03853798) in adult pts with PK deficiency who were not receiving regular transfusions. In this post hoc analysis, new PRO data are reported from ACTIVATE and its LTE study focusing on the impact of PK deficiency on work or school performance and how treatment with mitapivat impacts this over time in these pts. Methods: In the global, phase 3, placebo (PBO)-controlled ACTIVATE trial, adult pts with PK deficiency who were not receiving regular transfusions were randomized 1:1 to receive mitapivat (5/20/50 mg twice daily) or PBO for 24 weeks (wks). Pts who completed ACTIVATE were eligible to continue in the open-label LTE study, where all pts received mitapivat (5/20/50 mg twice daily or dose at last visit of ACTIVATE). Pts from ACTIVATE who participated in the LTE study were categorized into either the mitapivat-to-mitapivat arm (M/M) or the PBO-to-mitapivat arm (P/M). In the PKDIA questionnaire, pts who worked or went to school over the 7 days prior to a scheduled visit were asked to rate how often their PK deficiency interfered with their ability to perform to their full potential at work or school, using an 11-point numeric rating scale (work/school interference score; ranging from 0 [none of the time] to 10 [all of the time]). Changes in the work or school interference score from baseline (BL; defined as the last complete assessment before start of study treatment in ACTIVATE) were summarized descriptively by treatment arm over the fixed-dose period of ACTIVATE (24 wks) and up to Wk 60 of the LTE study (84 wks overall). Results: Among the 80 randomized adult pts with PK deficiency who were not receiving regular transfusions in ACTIVATE, 54 (67.5%) attended work/school at BL (28 pts randomized to mitapivat, 26 pts to PBO), 3 pts found it too difficult to attend, 21 did not attend for reasons unrelated to PK deficiency, and data were unavailable for 2. The mean (SD) work/school interference score for the 54 pts at BL was 4.0 (2.49) and was similar for the mitapivat (4.2 [2.42]) and PBO (3.9 [2.61]) arms. At Wk 24, 37 pts worked or went to school (including 22 in the mitapivat arm and 15 in the PBO arm), 5 pts found it too difficult to attend, 32 pts did not attend for reasons unrelated to PK deficiency, and data were unavailable for 6 pts. Change from BL in work/school interference score was compared for the 33 pts who attended work/school at both BL and Wk 24. Pts treated with mitapivat (n=19) had a reduction in the work/school interference score (mean [SD] change: -1.5 [1.74]) while negligible change (0.1 [2.41]) was observed among PBO pts (n=14). Notably, this reduction in score was sustained among M/M pts up to Wk 60 of the LTE. Furthermore, P/M pts experienced a reduction in the work or school interference score after starting mitapivat treatment in the LTE period, which was consistent with the improvements seen in the M/M arm during the ACTIVATE trial (Figure). Conclusions: In this post hoc analysis, interference in work or school performance was observed in adult pts with PK deficiency who were not receiving regular transfusions. Treatment with mitapivat showed sustained improvements in work or school performance over time. These data continue to support the potential for mitapivat to provide long-term benefits and reduced interference in work or school performance in these pts.

Tafamidis Efficacy Among Octogenarian Patients in the Phase 3 ATTR-ACT and Ongoing Long-Term Extension Study

BackgroundTafamidis was approved to treat patients with transthyretin amyloid cardiomyopathy (ATTR-CM) on the basis of findings from the phase 3 Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). ObjectivesThis study was a post hoc analysis exploring tafamidis efficacy in octogenarian patients. MethodsAnalysis of patients aged <80 and ≥80 years in ATTR-ACT and its ongoing open-label long-term extension (LTE) study, where all patients receive tafamidis. ResultsAfter 30 months in ATTR-ACT, least squares (LS) mean change from baseline in 6-minute walk test (6MWT) distance, N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration, and Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score were smaller (all P < 0.05) in patients aged ≥80 years treated with tafamidis (n = 51) vs placebo (n = 37). At the LTE study interim analysis, patients aged ≥80 years treated continuously with tafamidis had a smaller decline in KCCQ-OS score (P < 0.05) and trended toward longer median survival (45 vs 27 months; all-cause mortality HR: 0.6828 [95% CI: 0.4048-1.1517]; P = 0.1526) than those initially treated with placebo in ATTR-ACT. Similar efficacy was observed in patients aged <80 years in ATTR-ACT, including smaller LS mean change from baseline in 6MWT distance, NT-proBNP concentration, and KCCQ-OS score, and lower rate of cardiovascular-related hospitalizations with tafamidis (n = 125) vs placebo (n = 140). In the LTE study, patients aged <80 years treated continuously with tafamidis had a longer median survival (80 vs 41 months; HR = 0.4513 [95% CI: 0.3176-0.6413]; P < 0.0001) and a smaller decline in KCCQ-OS score than those initially treated with placebo. ConclusionsThe findings demonstrate tafamidis efficacy for patients with ATTR-CM both in those aged <80 and those aged ≥80 years. (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial [ATTR-ACT]; NCT01994889/Long-term Safety of Tafamidis in Subjects With Transthyretin Cardiomyopathy; NCT02791230)

Exploratory Tau Biomarker Results From a Multiple Ascending-Dose Study of BIIB080 in Alzheimer Disease

Accumulation of hyperphosphorylated, tangled microtubule-associated protein tau (MAPT) is a pathological hallmark of Alzheimer disease (AD) associated with disease progression and cognitive decline. To evaluate the effect of tau synthesis reduction on tau biomarkers in patients with mild AD. This randomized clinical trial was a double-blind, placebo-controlled 36-week multiple-ascending dose (MAD) phase 1b trial (October 2017 to September 2020), followed by a 64- or 71-week open-label long-term extension (LTE) (October 2019 to May 2022). After being assessed for eligibility at 12 sites in Canada and Europe, participants with mild AD and confirmed amyloid pathology were randomized 3:1 (BIIB080:placebo) in 4 dose cohorts. Intrathecal administration of BIIB080, a MAPT-targeting antisense oligonucleotide, or placebo. Active dose arms included 10 mg every 4 weeks, 30 mg every 4 weeks, 60 mg every 4 weeks, and 115 mg every 12 weeks during the MAD period and 60 mg every 12 weeks or 115 mg every 12 weeks during the LTE. The original primary end point was safety. Additionally, BIIB080, total tau (t-tau), and phosphorylated tau 181 (p-tau181) cerebrospinal fluid (CSF) concentrations were evaluated. Tau positron emission tomography (PET) was collected in a substudy, and standard uptake value ratios (SUVRs) were calculated in a priori-defined composite regions of interest. Of 102 participants assessed for eligibility, 46 participants with mild AD were enrolled; 23 (50%) were female, and mean (SD) age was 65.8 (5.70) years. BIIB080 was generally well tolerated and was associated with a dose-dependent reduction in CSF t-tau and p-tau181 in the MAD period (56% reduction; 95% CI, 50% to 62%; and 51% reduction; 95% CI, 38% to 63%, of CSF t-tau in the 2 higher-dose cohorts) that continued and/or was maintained through quarterly dosing in the LTE. Tau PET demonstrated reduced accumulation vs placebo at week 25 (n = 13). At week 100, tau PET showed a reduction from baseline across all regions assessed (n = 12), with the largest reductions from baseline observed in the temporal composite (-0.71 SUVR; 95% CI, -1.40 to -0.02). A moderate correlation was observed between model-predicted cumulative CSF drug exposure and tau PET change. In this randomized clinical trial, BIIB080 reduced tau biomarkers, including CSF t-tau, CSF p-tau181, and tau PET, which is associated with cognitive decline, in participants with mild AD. Effects of BIIB080 on biomarkers and clinical outcomes are being further evaluated in a phase 2 trial. ClinicalTrials.gov Identifier: NCT03186989.

Modeling of Treatment Outcomes with Tofacitinib Maintenance Therapy in Patients with Ulcerative Colitis: A Post Hoc Analysis of Data from the OCTAVE Clinical Program.

Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). This post hoc analysis assessed whether various statistical techniques could predict outcomes of tofacitinib maintenance therapy in patients with UC. Data from patients who participated in a 52-week, phaseIII maintenance study (OCTAVE Sustain) and an open-label long-term extension study (OCTAVE Open) were included in this analysis. Patients received tofacitinib 5 or 10mg twice daily (BID) or placebo (OCTAVE Sustain only). Logistic regression analyses were performed to generate models using clinical and laboratory variables to predict loss of responder status at week8 of OCTAVE Sustain, steroid-free remission (defined as a partial Mayo score of 0-1 in the absence of corticosteroid use) at week52 of OCTAVE Sustain, and delayed response at week8 of OCTAVE Open. Furthermore, differences in loss of response/discontinuation patterns between treatment groups in OCTAVE Sustain were established. The generated prediction models demonstrated insufficient accuracy for determining loss of response at week8, steroid-free remission at week52 in OCTAVE Sustain, or delayed response in OCTAVE Open. Both tofacitinib doses demonstrated comparable response/remission patterns based on visualizations of disease activity over time. The rectal bleeding subscore was the primary determinant of disease worsening (indicated by an increased total Mayo score), and the endoscopy subscore was the primary determinant of disease improvement (indicated by a decreased total Mayo score). Visualizations of disease activity subscores revealed distinct patterns among patients with UC that had disease worsening and disease improvement. The statistical models assessed in this analysis could not accurately predict loss of responder status, steroid-free remission, or delayed response to tofacitinib. Possible reasons include the small sample size or missing data related to yet unknown key variables that were not collected during these trials.

Matching-Adjusted Indirect Comparison of the Long-Term Efficacy of Deucravacitinib Versus Adalimumab for Moderate to Severe Plaque Psoriasis.

Deucravacitinib, an oral tyrosine kinase 2 (TYK2) inhibitor, is approved in the United States to treat adults with moderate-to-severe plaque psoriasis (PsO). This study compared the long-term efficacy of deucravacitinib and adalimumab using results from long-term extension (LTE) trials. Open-label LTE trials were identified for an indirect treatment comparison (deucravacitinib: POETYK PSO-LTE [NCT04036435]; adalimumab: REVEAL extension [NCT00195676]). To ensure study design comparability, patients initially randomized to placebo and switched to deucravacitinib or adalimumab after week 16 were compared. The primary outcome was an ≥ 75% reduction in Psoriasis Area and Severity Index score (PASI 75) at week 112 postrandomization. Secondary outcomes were PASI 75 at week 52 and an ≥ 90% reduction in PASI score (PASI 90) at weeks 52 and 112. Missing PASI data were imputed. A matching-adjusted indirect comparison was conducted; individual patient-level data from POETYK PSO-LTE were reweighted to balance baseline characteristics with those from the REVEAL extension. Before reweighting, on average, patients in the POETYK PSO-LTE (N = 329) versus the REVEAL (N = 345) extension were older, had a lower body weight, received more prior systemic treatments, and had higher baseline PASI scores and week 16 placebo PASI 75 and PASI 90 response rates. Following reweighting, adjusted week 112 PASI 75 response rates were significantly higher for deucravacitinib versus adalimumab (67.2% vs. 54.0%; mean difference [95% CI], 13.2 [4.0-22.5] percentage points). Deucravacitinib had a numerically higher adjusted week 112 PASI 90 response rate (41.3% vs. 34.0%; mean difference [95% CI], 7.3 [-2.0 to 16.7] percentage points). The treatments had similar week 52 adjusted PASI 75 and PASI 90 response rates. In this interim analysis, adults with moderate to severe PsO had higher long-term response rates at 2years when treated with deucravacitinib versus adalimumab. Deucravacitinib response rates remained stable whereas adalimumab response rates declined in year 2.

Efficacy and safety of CNM-Au8 in amyotrophic lateral sclerosis (RESCUE-ALS study): a phase 2, randomised, double-blind, placebo-controlled trial and open label extension.

CNM-Au8® is a catalytically-active gold nanocrystal neuroprotective agent that enhances intracellular energy metabolism and reduces oxidative stress. The phase 2, randomised, double-blind, placebo-controlled trial and open label extension RESCUE-ALS trial evaluated the efficacy and safety of CNM-Au8 for treatment of amyotrophic lateral sclerosis (ALS). RESCUE-ALS and its long-term open label extension (OLE) were conducted at two multidisciplinary ALS clinics located in Sydney, Australia: (i) the Brain and Mind Centre and (ii) Westmead Hospital. The double-blind portion of RESCUE-ALS was conducted from January 16, 2020 (baseline visit, first-patient first-visit (FPFV)) through July 13, 2021 (double-blind period, last-patient last-visit (LPLV)). Participants (N=45) were randomised 1:1 to receive 30mg of CNM-Au8 or matching placebo daily over 36 weeks in addition to background standard of care, riluzole. The primary outcome was mean percent change in summed motor unit number index (MUNIX), a sensitive neurophysiological biomarker of lower motor neuron function. Change in total (or summated) MUNIX score and change in forced vital capacity (FVC) were secondary outcome measures. ALS disease progression events, ALS Functional Rating Scale (ALSFRS-R) change, change in quality of life (ALSSQOL-SF) were assessed as exploratory outcome measures. Long-term survival evaluated vital status of original active versus placebo randomisation for all participants through at least 12 months following last-patient last-visit (LPLV) of the double-blind period. RESCUE-ALS and the open label study are registered in clinicaltrials.gov with registration numbers NCT04098406 and NCT05299658, respectively. In the intention-to-treat (ITT) population, there was no significant difference in the summated MUNIX score percent change (LS mean difference: 7.7%, 95% CI:-11.9 to 27.3%, p=0.43), total MUNIX score change (18.8, 95% CI:-56.4 to 94.0), or FVC change (LS mean difference: 3.6, 95% CI:-12.4 to 19.7) between the active and placebo treated groups at week 36. In contrast, survival analyses through 12-month LPLV demonstrated a 60% reduction in all-cause mortality with CNM-Au8 treatment [hazard ratio=0.408 (95% Wald CI: 0.166 to 1.001, log-rank p=0.0429). 36 participants entered the open label extension (OLE), and those initially randomised to CNM-Au8 exhibited a slower rate of disease progression, as measured by time to the occurrence of death, tracheostomy, initiation of non-invasive ventilatory support, or gastrostomy tube placement. CNM-Au8 was well-tolerated, and no safety signals were observed. CNM-Au8, in combination with riluzole, was well-tolerated in ALS with no identified safety signals. While the primary and secondary outcomes of this trial were not significant, the clinically meaningful exploratory results support further investigation of CNM-Au8 in ALS. The RESCUE-ALS was substantially funded by a grant from FightMND. Additional funding was provided by Clene Australia Pty Ltd.

Bleeding Patterns With Relugolix Combination Therapy in Women With Endometriosis-Associated Pain [ID: 1345374

INTRODUCTION: Relugolix combination therapy (Relugolix-CT: relugolix 40 mg, estradiol 1 mg, norethindrone acetate 0.5 mg) significantly improved endometriosis-associated pain versus placebo in the SPIRIT 1&amp;2 studies. Efficacy was maintained over 104 weeks in the long-term extension (LTE) study. Bleeding patterns in women treated up to 104 weeks with Relugolix-CT are reported. METHODS: SPIRIT 1&amp;2 were IRB-approved phase 3, 24-week, randomized studies of Relugolix-CT, delayed Relugolix-CT (relugolix 40 mg monotherapy followed by Relugolix-CT; 12 weeks each), or placebo in premenopausal women (age 18–50 years) with moderate-to-severe endometriosis-associated pain. Eligible women completing SPIRIT 1&amp;2 could enroll in the open-label LTE with once-daily Relugolix-CT. Bleeding days per cycle and bleeding patterns were recorded on eDiaries. Amenorrhea was defined as no bleeding over 28 consecutive days. RESULTS: Of 1,261 women originally randomized, 501 completed week 104. Baseline demographics and characteristics were balanced across treatment groups. The proportion of women achieving amenorrhea increased over time: 74.4% (95% CI 68.8–79.4) at week 24, and 82.3% (95% CI 74.6–88.4) at week 104. The average number of bleeding days per cycle (standard deviation) decreased over time from 5.8 (2.4) at baseline to 1.2 (3.3) at week 104. The number of heavy or extremely heavy bleeding days decreased from 1.9 at baseline to 0.0 at week 104. CONCLUSION: Treatment with Relugolix-CT in women with endometriosis-associated pain resulted in high rates of amenorrhea and complete elimination of heavy bleeding, thus demonstrating sustained benefit through 2 years. Findings may support patient counseling.

Evaluating the Effect of Sodium Phenylbutyrate and Taurursodiol on Survival Outcomes in Amyotrophic Lateral Sclerosis Using a Propensity Score–Matched Cohort From the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) Database (S33.005)

Evaluating the Effect of Sodium Phenylbutyrate and Taurursodiol on Survival Outcomes in Amyotrophic Lateral Sclerosis Using a Propensity Score–Matched Cohort From the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) Database (S33.005)

Effect of RIPK1 Inhibitor, SAR443820, on Serum Neurofilament Light Levels in Patients with Multiple Sclerosis: A Phase 2 Trial Design (P6-3.011)

Effect of RIPK1 Inhibitor, SAR443820, on Serum Neurofilament Light Levels in Patients with Multiple Sclerosis: A Phase 2 Trial Design (P6-3.011)

Deucravacitinib in plaque psoriasis: 2-year laboratory results from the phase 3 POETYK PSO program

Introduction: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved by the US Food and Drug Administration for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. In the phase 3 POETYK PSO-1 and PSO-2 trials, deucravacitinib was significantly more efficacious than placebo and apremilast and was well tolerated in moderate to severe plaque psoriasis. PSO-1 and PSO-2 completers could enroll in the ongoing open-label POETYK long-term extension (LTE) trial. Changes in blood laboratory parameters with deucravacitinib in the PSO-1, PSO-2, and LTE trials were compared with signature changes seen with JAK 1/2/3 inhibitors.&#x0D; Methods: The 52-week, double-blind PSO-1 (NCT03624127) and PSO-2 (NCT03611751) trials randomized adults with moderate to severe plaque psoriasis 2:1:1 to deucravacitinib 6 mg once daily, placebo, or apremilast 30 mg twice daily. At Week 52, eligible patients enrolled in POETYK LTE (NCT04036435) and received deucravacitinib. Changes from baseline in hematologic parameters (lymphocytes, neutrophils, platelets, hemoglobin) and lipid and chemistry parameters (cholesterol, creatinine, CPK, ALT) were assessed through Week 100 (LTE Week 48). CTCAE grade ≥3 laboratory abnormalities and treatment discontinuations due to laboratory abnormalities were evaluated.&#x0D; Results: 1519 patients received ≥1 dose of deucravacitinib in all 3 trials. In total, 1179 (77.6%) and 584 (38.4%) patients had ≥52 and ≥104 weeks, respectively, of continuous deucravacitinib exposure; median duration of exposure was 682.0 days (97 weeks). No trends in clinically meaningful changes from baseline were observed in these parameters from Weeks 0–52 or in the LTE. Grade 3 or 4 abnormalities over 100 weeks of deucravacitinib treatment were rare, with incidence rates comparable to placebo and apremilast through Week 52; no increases were seen in the LTE. Two patients discontinued deucravacitinib due to lymphopenia and abnormal hepatic function.&#x0D; Conclusion: No trends in clinically meaningful changes from baseline were observed with deucravacitinib in laboratory parameters, including signature changes associated with JAK 1/2/3 inhibitors. Treatment discontinuations and grade 3 or 4 laboratory abnormalities were rare and comparable to incidence rates seen with placebo and apremilast. These results suggest laboratory monitoring is not warranted with deucravacitinib.

Matching-adjusted indirect comparison (MAIC) of deucravacitinib versus adalimumab for the treatment of patients with moderate to severe plaque psoriasis over 2 years

Introduction: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor, is approved in the US for the treatment of adults with moderate to severe plaque psoriasis (PsO). A previous indirect treatment study showed comparable efficacy between deucravacitinib and first-generation biologics at week 52. The objective of this study was to compare the long-term efficacy of deucravacitinib to that of adalimumab based on long-term extension (LTE) trials, after adjusting for differences in patient characteristics at baseline. &#x0D; Methods: Open-label LTE trials that were feasible for indirect treatment comparison were identified for each treatment (deucravacitinib: POETYK PSO-LTE [NCT04036435]; adalimumab: REVEAL extension [NCT00195676]). Patients who were initially randomized to placebo and switched to continuous active treatment after Week 16 were selected as cohorts due to the comparability of study design and outcomes of interest. Patients with prior adalimumab were excluded from the deucravacitinib cohort. The primary outcome was PASI 75 at Week 112 since randomization and secondary outcomes were PASI 75 at Week 52 and PASI 90 at Weeks 52 and 112; missing PASI data was imputed using the last observation carried forward (LOCF) method. Matching-adjusted indirect comparison was conducted where individual patient-level data from POETYK PSO-LTE were reweighted to achieve balance with the summary baseline characteristics in the REVEAL extension trial: age, sex, race, weight, duration of psoriasis, body surface area affected, prior treatment history, baseline PASI and placebo PASI 75/90 responses at Week 16. Sensitivity analyses explored the effect of adjusting for prior treatment or not as well as history of psoriatic arthritis and patient's overall severity of disease.&#x0D; Results: Patients from POETYK PSO-LTE (N=329) were on average older, with lower weight, but with more prior systemic treatment exposure, higher baseline PASI score and higher placebo PASI 75/90 response at Week 16 than those in REVEAL (N=345). After adjustment, baseline differences between the two trials were mitigated. Results showed adjusted PASI 75 and PASI 90 response rate at Week 112 since randomization was higher for patients who were treated with deucravacitinib compared to those who were treated with adalimumab after 16 weeks of placebo: PASI 75= 67.2% vs 54% (mean difference [95% CI]= 13.2% [4, 22.5]); PASI 90= 41.3% vs 34% (7.3% [-2, 16.7]). Adjusted PASI 75 and PASI 90 at Week 52 were similar between the two cohorts. Results from the sensitivity analyses confirmed the base case findings.&#x0D; Conclusion: This indirect comparison analysis suggests that patients with moderate to severe plaque psoriasis with continuous active treatment on deucravacitinib had better long-term response than adalimumab and highlights the therapeutic role of deucravacitinib.

Population pharmacokinetics of duloxetine in Japanese pediatric patients with major depressive disorder

The objectives of this analysis were to characterize the pharmacokinetics of duloxetine in Japanese pediatric patients aged 9–17 years with major depressive disorder (MDD) and to explore potential intrinsic factors affecting its pharmacokinetics. A population pharmacokinetic (PK) model was developed with plasma steady-state duloxetine concentrations from Japanese pediatric patients with MDD in an open-label long-term extension trial in Japan (ClinicalTrials.gov Identifier: NCT03395353). Duloxetine pharmacokinetics in Japanese pediatric patients was well described by a one-compartment model with first-order absorption. The population mean estimates of CL/F and V/F of duloxetine were 81.4 L/h and 1170 L, respectively. Patient intrinsic factors were assessed for their potential influence on duloxetine apparent clearance (CL/F). Only sex was identified as a statistically significant covariate of duloxetine CL/F. Duloxetine pharmacokinetic parameters and model-predicted duloxetine concentrations at steady state in the Japanese pediatric population were compared with those in Japanese adults. The mean duloxetine CL/F in pediatrics is slightly higher than adults, it is, however, expected that comparable steady-state duloxetine exposure in pediatric patients can be achieved with the approved dose regimen for adults. The population PK model provides useful information to understand the pharmacokinetic characteristics of duloxetine for Japanese pediatric patients with MDD. ClinicalTrials.gov identifierNCT03395353

Interim Analysis of Safety and Hematological Parameters of an Ongoing Long-Term Open-Label Extension Study of Investigational PI3Kδ Inhibitor Leniolisib for Patients with Activated PI3K Delta Syndrome (APDS) through December 2021

Interim Analysis of Safety and Hematological Parameters of an Ongoing Long-Term Open-Label Extension Study of Investigational PI3Kδ Inhibitor Leniolisib for Patients with Activated PI3K Delta Syndrome (APDS) through December 2021

S1023 Assessment of Health-Related Quality of Life and Patient-Reported Outcomes With Tofacitinib Treatment Stratified by Age in Patients From the OCTAVE Ulcerative Colitis Clinical Program

S1023 Assessment of Health-Related Quality of Life and Patient-Reported Outcomes With Tofacitinib Treatment Stratified by Age in Patients From the OCTAVE Ulcerative Colitis Clinical Program

33006 Long-term improvement of patient-reported outcomes in adult patients with atopic dermatitis treated with baricitinib in the US and Canada

Objective: To evaluate long-term patient-reported outcome (PRO) improvements in patients with atopic dermatitis (AD) treated with baricitinib, a Janus kinase (JAK)1/JAK2 inhibitor. Methods: Data were derived from 2 phase 3 studies: double-blind placebo-controlled BREEZE-AD5 (NCT03435081) and long-term open-label extension BREEZE-AD6 (NCT03559270) through 52 weeks of treatment. Low-potency topical corticosteroids were permitted after Week 16 in BREEZE-AD5 and throughout BREEZE-AD6. PROs [Dermatology Life Quality Index (DLQI), Patient-Oriented Eczema Measure (POEM), and Hospital Anxiety Depression Scale (HADS-anxiety and HADS-depression)] were assessed to Week 52 using descriptive statistics with missing data imputed by last observation carried forward. Results: In 146 patients receiving baricitinib 2 mg, the quality of life measure DLQI (mean ± standard deviation at baseline 15.0 ± 7.6) showed a mean change from baseline of −7.0 ± 8.2 at Weeks 48-52. Patient-reported improvements in skin symptoms as measured by POEM were −7.3 ± 8.8 at Weeks 48-52 from mean baseline value of 21.7 ± 5.4. By Weeks 48-52, 68.9% and 57.6% of patients had achieved a clinically meaningful ≥4-point improvement in DLQI and POEM, respectively. HADS-anxiety and HADS-depression scores were 7.0 ± 4.4 and 5.2 ± 4.3 at baseline, respectively, with patients reporting a change from baseline of −1.9 ± 3.7 and −1.8 ± 3.3 at Weeks 48-52. Conclusion: Patients with moderate to severe AD treated with baricitinib 2 mg experienced clinically meaningful PRO improvements in skin symptoms, quality of life, and anxiety and depression over 52 weeks.

Clostridium difficile Infection in Patients with Ulcerative Colitis Treated with Tofacitinib in the Ulcerative Colitis Program.

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Patients with inflammatory bowel disease are susceptible to Clostridium difficile infection (CDI). Here, we evaluate CDI in the tofacitinib UC clinical program. Events from 4 randomized, placebo-controlled studies (phase [P] 2 or P3 induction [NCT00787202; NCT01465763; NCT01458951], P3 maintenance [NCT01458574]) and an open-label, long-term extension (OLE) study (NCT01470612), were analyzed as 3 cohorts: Induction (P2/P3 induction), Maintenance (P3 maintenance), and Overall (patients receiving tofacitinib 5 or 10 mg twice daily [BID] in P2, P3, and OLE studies; including final data from the OLE study, as of August 24, 2020). Proportions and incidence rates (unique patients with events per 100 patient-years of exposure) of CDI were evaluated. The overall cohort comprised 1157 patients who received ≥1 dose of tofacitinib 5 or 10 mg BID, with a total of 2814.4 patient-years of tofacitinib exposure and up to 7.8 years of treatment. A total of 82.6% of patients received predominantly tofacitinib 10 mg BID. In the induction, maintenance, and overall cohorts, 3 (2 tofacitinib treated, 1 placebo treated), 3 (all placebo treated), and 9 patients had CDI, respectively; the overall cohort incidence rate was 0.31 (95% confidence interval, 0.14-0.59). CDI were all mild-moderate in severity and resolved with treatment in 8 patients. Six of 9 patients continued tofacitinib treatment without interruption. Two patients had events reported as serious due to hospitalization. Two patients were receiving corticosteroids when the CDI occurred. CDIs among patients with UC receiving tofacitinib were infrequent, cases were mild-moderate in severity, and most resolved with treatment.

Long-term evaluation of the safety and efficacy of recombinant human pentraxin-2 (rhPTX-2) in patients with idiopathic pulmonary fibrosis (IPF): an open-label extension study

BackgroundRecombinant human pentraxin-2 (rhPTX-2) significantly decreased decline in percent predicted forced vital capacity (FVC) and stabilized 6-min walk distance (6MWD) in patients with idiopathic pulmonary fibrosis (IPF) during the 28-week, placebo-controlled, randomized period of the Phase II PRM-151–202 study. Interim (76-week) data from the open-label extension (OLE) demonstrated sustained safety and efficacy with rhPTX-2 treatment. Here, we present the entire long-term OLE safety and efficacy data to 128 weeks.MethodsPatients who completed the randomized PRM-151–202 study period were eligible for the OLE, during which all patients received rhPTX-2, having started rhPTX-2 (i.e., crossed from placebo) or continued rhPTX-2 after Week 28. rhPTX-2 was administered in 28-week cycles, with 10 mg/kg intravenous infusions (60 min) on Days 1, 3, and 5 in the first week of each cycle, then one infusion every 4 weeks up to Week 128. The OLE primary objective was to assess the long-term safety and tolerability of rhPTX-2. Other outcomes included FVC, 6MWD, and patient-reported outcomes (descriptive analysis).ResultsAll 111 patients who completed the randomized period entered the OLE (n = 37 started rhPTX-2; n = 74 continued rhPTX-2); 57 (51.4%) completed to Week 128. The treatment-emergent adverse event (TEAE) profile was consistent with the randomized period, with the majority of TEAEs graded mild or moderate. Serious TEAEs occurred in 47 patients (42.3%), most frequently IPF (n = 11; 9.9%), pneumonia (n = 7; 6.3%), and acute respiratory failure (n = 3; 2.7%). Three patients underwent lung transplantation. Most serious TEAEs (and all 14 fatal events) were considered unrelated to rhPTX-2 treatment. For patients starting vs continuing rhPTX-2, mean (95% confidence interval) changes from baseline to Week 128 were, respectively, − 6.2% (− 7.7; − 4.6) and − 5.7% (− 8.0; − 3.3) for percent predicted FVC and − 36.3 m (− 65.8; − 6.9) and − 28.9 m (− 54.3; − 3.6) for 6MWD; however, conclusions were limited by patient numbers at Week 128.ConclusionsLong-term treatment (up to 128 weeks) with rhPTX-2 was well tolerated in patients with IPF, with no new safety signals emerging in the OLE. The limited efficacy data over 128 weeks may suggest a trend towards a treatment effect.Trial registration NCT02550873; EudraCT 2014-004782-24.