Open-label Extension Study Research Articles

Efficacy of long-term risankizumab treatment for moderate-to-severe plaque psoriasis: Subgroup analyses by baseline characteristics and psoriatic disease manifestations through 256 weeks (LIMMitless trial).

Psoriasis is an inflammatory skin disease that impacts a heterogeneous group of patients and can have multiple clinical manifestations. Risankizumab is approved for the treatment of moderate-to-severe plaque psoriasis. To evaluate the long-term efficacy of risankizumab according to baseline patient characteristics, and for the treatment of high-impact disease manifestations (nail, scalp and palmoplantar psoriasis), through 256 weeks of continuous treatment in the phase 3 LIMMitless study. This subgroup analysis evaluated pooled data from patients with moderate-to-severe plaque psoriasis who were randomized to risankizumab 150 mg during two double-blind, phase 3, 52-week base studies (UltIMMa-1/2; NCT02684370/NCT02684357) and were enrolled in the phase 3 LIMMitless open-label extension study (NCT03047395). Subgroup assessments included the proportion of patients who achieved ≥90%/100% improvement in Psoriasis Area and Severity Index (PASI 90/100). Among patients with nail, scalp and/or palmoplantar psoriasis in addition to skin psoriasis, assessments included changes from baseline in and resolution of these three psoriatic manifestations. Overall, a numerically similar proportion of patients (N = 525) achieved PASI 90/100 through Week 256, regardless of their baseline age, sex, body mass index, weight, PASI or psoriatic arthritis status. Patients with nail, scalp and/or palmoplantar psoriasis experienced substantial improvements in manifestation-specific indices (mean improvement from baseline to Week 256 of >81%, >94% and >97%, respectively); in patients with all three manifestations (N = 121), 44.6% achieved complete clearance of these manifestations at Week 256. Risankizumab demonstrated generally consistent efficacy through 256 weeks across patient subgroups and showed durable long-term efficacy for psoriatic disease manifestations.

Long-term safety and efficacy of zilucoplan in patients with generalized myasthenia gravis: interim analysis of the RAISE-XT open-label extension study.

Generalized myasthenia gravis (gMG) is a chronic, unpredictable disease associated with high treatment and disease burdens, with a need for more effective and well-tolerated treatments. To evaluate the long-term safety, tolerability, and efficacy of zilucoplan in a mild-to-severe, acetylcholine receptor autoantibody-positive (AChR+) gMG population. Ongoing, multicenter, phase III open-label extension (OLE) study. Eligible patients had completed a qualifying randomized, placebo-controlled phase II or phase III zilucoplan study and received daily, self-administered subcutaneous 0.3 mg/kg zilucoplan. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Secondary efficacy endpoints included change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score. In total, 200 patients enrolled. At the cut-off date (8 September 2022), median (range) exposure to zilucoplan in RAISE-XT was 1.2 (0.11-4.45) years. Mean age at OLE baseline was 53.3 years. A total of 188 (94%) patients experienced a TEAE, with the most common being MG worsening (n = 52, 26%) and COVID-19 (n = 49, 25%). In patients who received zilucoplan 0.3 mg/kg in the parent study, further improvements in MG-ADL score continued through to Week 24 (least squares mean change [95% confidence interval] from double-blind baseline -6.06 [-7.09, -5.03]) and were sustained through to Week 60 (-6.04 [-7.21, -4.87]). In patients who switched from placebo in the parent study, rapid improvements in MG-ADL score were observed at the first week after switching to zilucoplan; further improvements were observed at Week 24, 12 weeks after switching (-6.46 [-8.19, -4.72]), and were sustained through to Week 60 (-6.51 [-8.37, -4.65]). Consistent results were observed in other efficacy endpoints. Zilucoplan demonstrated a favorable long-term safety profile, good tolerability, and sustained efficacy through to Week 60 with consistent benefits in a broad AChR+ gMG population. Additional long-term data will be available in future analyses. ClinicalTrials.gov identifier: NCT04225871 (https://clinicaltrials.gov/ct2/show/NCT04225871).

Risankizumab: Mechanism of action, clinical and translational science.

Risankizumab is a high-affinity neutralizing anti-interleukin (IL)-23 monoclonal antibody marketed in over 40 countries across the globe to treat several inflammatory diseases, such as plaque psoriasis (PsO), psoriatic arthritis (PsA), and Crohn's disease (CD). This paper reviews the regulatory approval, mechanism of action, pharmacokinetics (PKs)/pharmacodynamics, immunogenicity, and clinical efficacy and safety data for risankizumab, focusing on the three main approved indications. Risankizumab binds to the p19 subunit of IL-23 and inhibits IL-23 from interacting with the IL-23 receptor and subsequent signaling. Biomarker data obtained following treatment with risankizumab in multiple indications provided supportive evidence for downstream blockade of IL-23 signaling associated with disease pathology. The PKs of risankizumab is linear and time-independent, consistent with typical IgG1 monoclonal antibodies, across all evaluated indications. Risankizumab exhibited positive exposure-response relationships for efficacy with no apparent exposure-dependent worsening in safety. Immunogenicity to risankizumab had no major clinical consequences for either efficacy or safety. Efficacy and safety of risankizumab have been established in PsO, PsA, and CD in the pivotal clinical trials where superior benefit/risk profiles were demonstrated compared to placebo and/or active comparators. Moreover, safety evaluations in open-label extension studies following long-term treatment with risankizumab showed stable and favorable safety profiles consistent with shorter-term studies. These data formed the foundation for risankizumab's marketing approvals to treat multiple inflammatory diseases across the globe.

Dupilumab sustains lung function improvements in patients with moderate-to-severe asthma

BackgroundTRAVERSE (NCT02134028), a phase 3 open-label extension study, assessed dupilumab safety and efficacy in patients with asthma aged ≥12 years who completed a previous dupilumab asthma study. This analysis evaluated changes in multiple lung function parameters in patients with moderate-to-severe asthma with elevated type 2 biomarkers (baseline eosinophils ≥150 cells·μL−1 or fractional exhaled nitric oxide ≥25 ppb) who completed QUEST (parent study) and 2 years of dupilumab treatment in TRAVERSE. MethodsEndpoints analyzed included: pre-bronchodilator forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), forced expiratory flow (FEF25-75 %), and pre- and post-bronchodilator FEV1/FVC at parent study baseline (PSBL) at Weeks 0, 2, 48, and 96 in TRAVERSE, as well as pre- and post-bronchodilator FEV1 slopes in QUEST and TRAVERSE. Statistical analyses were descriptive. ResultsDupilumab improved pre-bronchodilator FEV1, FVC, and FEF25–75 % in QUEST; these improvements were sustained in TRAVERSE. In QUEST patients who received placebo, dupilumab initiation in TRAVERSE resulted in rapid lung function improvements. Mean (standard deviation) changes from PSBL at TRAVERSE Weeks 48 and 96 in pre-bronchodilator FEV1 were 0.52 (0.59) and 0.45 (0.49) L in the dupilumab/dupilumab group and 0.47 (0.42) and 0.44 L (0.45) in the placebo/dupilumab group, respectively. Similar trends were observed for FVC and FEF25–75 %. Dupilumab also improved FEV1 slopes in QUEST and TRAVERSE. ConclusionDupilumab demonstrated sustained improvements across multiple spirometric lung function measurements for up to 3 years; patients who received placebo in QUEST experienced rapid lung function improvement upon initiation of dupilumab in TRAVERSE.

Exploring concurrent validity of the CLN2 Clinical Rating Scale: Comparison to PedsQL using cerliponase alfa clinical trial data.

The CLN2 Clinical Rating Scale evaluates disease progression in CLN2 disease, an ultra-rare, neurodegenerative disorder with late infantile onset. To validate the Clinical Rating Scale, a comparison with the Pediatric Quality of Life Inventory (PedsQL) was conducted utilising clinical trial data investigating cerliponase alfa use in CLN2 disease. Linear regression and mixed effects models were used to investigate the relationship between the Clinical Rating Scale and PedsQL using open-label, single-arm, phase 1/2 (NCT01907087) and ongoing extension study (NCT02485899) data of 23 children with CLN2 disease treated with cerliponase alfa for ≥96 weeks. Correlations between the four Clinical Rating Scale domains were low. Linear mixed effects analyses showed significant correlation between PedsQL and Clinical Rating Scale (Total score or motor-language [ML] score adjusted p-values <0.05), driven by the relationship with the PedsQL Physical domain. A statistically significant relationship was identified between the Clinical Rating Scale motor domain and PedsQL (Total score: adjusted p-value = 0.048, parameter estimate [PE] = 8.10; Physical domain score: adjusted p-value = 0.012; PE = 13.79). Each domain of the Clinical Rating Scale provides unique information on disease state. Validity of the scale is supported by its relationship with the PedsQL. Among the four domains of the Clinical Rating Scale, motor has the highest correlation to PedsQL, suggesting motor function as a driver of patients' quality of life. The lack of association between the remaining domains of the Clinical Rating Scale and PedsQL suggests that additional disease-specific measures may be needed to fully capture the quality of life impact of CLN2 disease. NCT01907087, NCT02485899.

Safety and efficacy of cerliponase alfa in children with neuronal ceroid lipofuscinosis type 2 (CLN2 disease): an open-label extension study

Cerliponase alfa is a recombinant human tripeptidyl peptidase 1 (TPP1) enzyme replacement therapy for the treatment of neuronal ceroid lipofuscinosis type 2 (CLN2 disease), which is caused by mutations in the TPP1 gene. We aimed to determine the long-term safety and efficacy of intracerebroventricular cerliponase alfa in children with CLN2 disease. This analysis includes cumulative data from a primary 48-week, single-arm, open-label, multicentre, dose-escalation study (NCT01907087) and the 240-week open-label extension with 6-month safety follow-up, conducted at five hospitals in Germany, Italy, the UK, and the USA. Children aged 3-16 years with CLN2 disease confirmed by genetic analysis and enzyme testing were eligible for inclusion. Treatment was intracerebroventricular infusion of 300 mg cerliponase alfa every 2 weeks. Historical controls with untreated CLN2 disease in the DEM-CHILD database were used as a comparator group. The primary efficacy outcome was time to an unreversed 2-point decline or score of 0 in the combined motor and language domains of the CLN2 Clinical Rating Scale. This extension study is registered with ClinicalTrials.gov, NCT02485899, and is complete. Between Sept 13, 2013, and Dec 22, 2014, 24 participants were enrolled in the primary study (15 female and 9 male). Of those, 23 participants were enrolled in the extension study, conducted between Feb 2, 2015, and Dec 10, 2020, and received 300 mg cerliponase alfa for a mean of 272·1 (range 162·1-300·1) weeks. 17 participants completed the extension and six discontinued prematurely. Treated patients were significantly less likely than historical untreated controls to have an unreversed 2-point decline or score of 0 in the combined motor and language domains (hazard ratio 0·14, 95% CI 0·06 to 0·33; p<0·0001). All participants experienced at least one adverse event and 21 (88%) experienced a serious adverse event; nine participants experienced intracerebroventricular device-related infections, with nine events in six participants resulting in device replacement. There were no study discontinuations because of an adverse event and no deaths. Cerliponase alfa over a mean treatment period of more than 5 years was seen to confer a clinically meaningful slowing of decline of motor and language function in children with CLN2 disease. Although our study does not have a contemporaneous control group, the results provide crucial insights into the effects of long-term treatment. BioMarin Pharmaceutical.

Maintenance of the synergistic effects of cord blood cells and erythropoietin combination therapy after additional cord blood infusion in children with cerebral palsy: 1-year open-label extension study of randomized placebo-controlled trial

BackgroundThis 1-year open-label extension study aimed to identify the persistent synergistic effects of allogeneic umbilical cord blood (UCB) cells and erythropoietin (EPO) in children with cerebral palsy (CP) for up to 2 years.MethodsThis open-label extension study followed children with CP who were enrolled in the previous randomized, double blind, placebo-controlled trial. The following groups from the first trial were maintained: (A) UCB + EPO, (B) UCB, (C) EPO, and (D) only placebo, and all the participants had continued active rehabilitation. This extended study started 3 months after termination of the first trial, which had a 1-year follow-up duration. All subjects received single additional UCB intravenous infusion at the extension baseline regardless of their initial allocation. Outcome measures were the gross motor performance measure (GMPM), gross motor function measure-66 (GMFM-66), and Bayley scales of infant development-II (BSID-II), which were followed at 3, 6, and 12 months after the extension baseline. Changes in the outcome scores from the baseline values of the previous trial and this study were analysed.ResultsSixty-nine children (4.29 ± 1.28 years, M:F = 34:35) were included in this study. Each group showed improvements in the outcome measures at 12 months after additional UCB infusion compared to the baseline scores, except for GMFM and GMPM in Group C which were elevated at 3 and 6 months post-therapy. Total subject analyses did not show significant differences in the outcome measures between the four different groups at 3, 6 and 12 months after additional UCB therapy. However, patients with severe dysfunction, whose GMFCS levels were IV and V, revealed a larger improvement of the GMPM score in Group A than in Group D (Ps < 0.05) from the baseline value of the previous trial. The changes in BSID-II mental scale scores were positively correlated with the number of administered total nucleated cells per unit body weight during this one-year extension study period (r = 0.536, P = 0.001).ConclusionsThese results suggest that when administering UCB to treat patients with CP, combination therapy with EPO is more effective, and the effect might last as long as 2 years, especially in patients with severe impairments.Trial registration: CHA Bundang Medical Center IRB, No. 2015–06-093, approved on July 29, 2015, (https://www.e-irb.com:3443/devlpg/nlpgS200.jsp), ClinicalTrials.gov, NCT03130816, retrospectively registered on April 27, 2017 (https://clinicaltrials.gov/ct2/show/NCT03130816?term=NCT03130816&draw=2&rank=1).

What Is in the Neuromuscular Junction Literature?

Abstract This update covers several articles on diagnosis and misdiagnosis of myasthenia gravis (MG), the role of complement in MG, and then an impressive number of recent treatment trials. There is a negative study on any corticosteroid-sparing effect of intravenous immunoglobulin. A number of positive studies are reviewed. Open-label extension studies of phase 3 trials showed benefit regarding quality of life with efgartigimod and in functional measures with ravulizumab. The phase 3 RAISE trial of zilucoplan, a self-administered complement C5 inhibitor, is covered as well as the MyCarinG trial of rozanolixizumab. The notion of using fast-acting therapies early in the course of MG is addressed. The last sections center on MG and Lambert–Eaton myasthenic syndrome as a consequence of immune checkpoint inhibitor therapy.

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.

A Real-World Evidence Review of Post-Marketing Safety and Compliance with Pegcetacoplan in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) in the US

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic condition characterized by complement-mediated, life-threatening hemolysis and thrombosis which are associated with significant impacts on health-related quality of life (HRQoL). Pegcetacoplan is the first targeted complement component 3 (C3) therapy approved for adults with PNH (US) and adults with PNH plus anemia despite receiving a complement component 5 inhibitor (C5i) for ≥3 months (EU). In clinical trials including patients with PNH who were C5i-experienced or -naive, pegcetacoplan significantly improved levels of hemoglobin (Hb) and lactate dehydrogenase (LDH) and reduced transfusion burden. Pegcetacoplan had a favorable safety profile in parent studies and an ongoing long-term, rollover, open-label extension study (NCT03531255). Compliance with pegcetacoplan treatment was high across all clinical studies. In the US real-world OPERA and Adelphi PNH Disease Specific Programme™ (DSP) patient-reported outcomes (PRO) studies, improvements in levels of Hb and LDH, along with self-reported fatigue and cognitive outcomes, were observed. Pegcetacoplan treatment also led to reductions in the frequency and severity of PNH symptoms (including shortness of breath and fatigue) and improvements in social, physical, and emotional HRQoL domains in the US real-world Voice of the Patient PRO study. Further, both patient and physician satisfaction with pegcetacoplan treatment was high in the Adelphi PNH DSP study. However, to date, compliance and safety with pegcetacoplan treatment in the real-world setting have not been described. The objective of this real-world evidence review study was to evaluate compliance and safety with pegcetacoplan treatment in patients with PNH in the US post-marketing setting. Methods: Post-marketing data from the US, including the number of patients who received pegcetacoplan and reported safety events, were collected and analyzed from the pegcetacoplan Risk Evaluation and Mitigation Strategies (REMS) program which controls the distribution of pegcetacoplan and the pharmacovigilance safety database through May 13, 2023. Treatment compliance was calculated as the proportion of days a patient had the drug in possession, divided by the total number of days of follow-up, using central pharmacy prescription refill data. Thrombosis (a leading cause of death in patients with PNH prior to the availability of complement inhibitors) and meningococcal infections (a potential risk with complement inhibitors) were safety events of interest. To reduce the risk of serious meningococcal infections, clinical trial protocols and pegcetacoplan labeling required vaccination against Streptococcus pneumoniae; N meningitidis types A, C, W, Y, and B; and Haemophilus influenzae type B before starting treatment with pegcetacoplan. If pegcetacoplan treatment must be initiated before vaccination, the US label mandates prophylactic antibiotic use. In this study, the rates of thrombosis and meningococcal infection per 100 patient-years were estimated based on the total number of thrombosis and meningococcal infection events reported in the REMS program. Results: As of May 13, 2023, the cumulative pegcetacoplan exposure was 273.10 patient-years in the US post-marketing setting. Based on prescription refill data, compliance with pegcetacoplan treatment was ~98%. There were 2 confirmed thrombotic events reported and the incidence of thrombotic events was 0.73 events/100 patient-years in 273.10 patient-years. Similar to clinical trials, no meningococcal infections were reported in the US post-marketing setting. Conclusions: The high compliance rate and favorable safety profile of pegcetacoplan in the US post-marketing setting were consistent with clinical trial observations. These data, coupled with the effectiveness on hematologic parameters and improvements in symptoms and HRQoL reported in pegcetacoplan real-world PRO studies, support a positive benefit:risk profile for pegcetacoplan in the real-world setting.

Impact of dupilumab across seasons in patients with type 2, uncontrolled, moderate-to-severe asthma

BackgroundSeasonal variability could influence asthma exacerbations. Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin (IL)-4/IL-13, key and central drivers of type 2 inflammation. In the 52-week QUEST study (NCT02414854), add-on dupilumab every 2 weeks vs placebo significantly reduced exacerbations and improved prebronchodilator forced expiratory volume in 1 second in patients with uncontrolled, moderate-to-severe asthma. TRAVERSE (NCT02134028), the open-label QUEST extension study, enrolled patients with moderate-to-severe asthma to investigate long-term safety and efficacy of dupilumab, including patients who previously received placebo that initiated dupilumab therapy. ObjectiveTo investigate long-term dupilumab efficacy in reducing exacerbations across yearly seasons in patients with type 2 inflammatory asthma with and without clinical evidence of allergic asthma. MethodsUnadjusted annualized exacerbation rate and proportions of patients experiencing severe asthma exacerbations are reported by month and season and for both hemispheres. ResultsThe proportion of patients with type 2 asthma experiencing 1 or more severe asthma exacerbations during QUEST was 20.8% vs 10.0% in spring, 18.2% vs 7.3% in summer, 22.2% vs 12.6% in autumn, and 26.4% vs 12.0% in winter, for placebo- vs dupilumab-treated patients, respectively; P was less than .001 for placebo vs dupilumab in all seasons. Reductions in the proportion of patients experiencing severe exacerbations across seasons in subgroups with and without evidence of allergic asthma were similar to the overall type 2 population. Reductions in severe exacerbations observed during QUEST were sustained during TRAVERSE, up to 96 weeks across both hemispheres. ConclusionDupilumab reduced asthma exacerbations, with no difference in the reduction between seasons, in patients with type 2 inflammation, with and without evidence of allergic asthma. Trial RegistrationClinicalTrials.gov Identifiers: NCT02414854, NCT02134028.

Maintenance of Clinical Response With Continued Risankizumab Treatment for Moderate-to-Severe Psoriasis Through 304 Weeks: Interim Analysis of the LIMMitless Open-Label Extension Study

Introduction: Interleukin (IL)-23 is a key regulator of plaque psoriasis pathogenesis. Risankizumab, a humanized immunoglobulin G1 monoclonal antibody that specifically inhibits IL-23 by binding to its p19 subunit, is approved for the treatment of moderate-to-severe plaque psoriasis in adults; however, additional data on long-term maintenance of efficacy with risankizumab treatment are needed. Here we report on the maintenance of clinical response through 304 weeks of continuous risankizumab treatment.&#x0D; Methods: In this interim analysis, we evaluated patients with moderate-to-severe plaque psoriasis who were randomized to receive risankizumab 150 mg at weeks 0, 4, and 16 and every 12 weeks thereafter during 2 double‑blind, phase 3, 52-week base studies (UltIMMa 1 [NCT02684370] and UltIMMa 2 [NCT02684357]) and enrolled in LIMMitless, an ongoing, phase 3, multicenter, single‑arm, open-label extension (OLE) study (NCT03047395) evaluating the long-term safety and efficacy of continuous risankizumab 150 mg treatment every 12 weeks for plaque psoriasis. Safety was assessed through ≤ 324 weeks by monitoring of treatment‑emergent adverse events through the data cutoff date (May 22, 2023). Efficacy was assessed by the proportion of patients who maintained ≥ 90% or 100% improvement from baseline in Psoriasis Area and Severity Index (PASI 90/100) during LIMMitless and mean improvement in PASI from baseline of the UltIMMa-1/2 study through 252 additional weeks in the LIMMitless study (total of 304 weeks). Missing efficacy data were imputed using modified nonresponder imputation (mNRI), last observation carried forward (LOCF), or observed cases (OC) methodology.&#x0D; Results: A total of 525 patients were randomized to receive risankizumab 150 mg treatment for 52 weeks in the UltlMMa‑1/2 studies and continued open-label risankizumab 150 mg treatment in the LIMMitless OLE study. Risankizumab was well tolerated through ≤ 324 weeks; no new safety concerns were reported in patients with moderate-to-severe plaque psoriasis. At OLE entry, most patients (451, 85.9%) achieved PASI 90; of those, 422 (93.6%) maintained PASI 90 through week 304 by mNRI (LOCF, 92.7%; OC, 93.8%). Of 320 patients (61.0%) who achieved PASI 100 at OLE entry, 209 (65.3%) maintained PASI 100 through week 304 by mNRI (LOCF, 80.6%; OC, 79.9%). Mean PASI improvement from baseline was generally consistent from OLE entry (95.6% for both LOCF and OC) through week 304 (LOCF, 95.9%; OC, 96.5%).&#x0D; Conclusion: In this 304-week interim analysis of continuous risankizumab treatment, the safety profile was consistent with previous interim analyses from the LIMMitless study. With continuous risankizumab treatment, most patients maintained PASI 90 or PASI 100 responses from OLE entry through 252 additional weeks in the LIMMitless study.

Spesolimab for Hidradenitis Suppurativa: A Proof-of-Concept Study

Introduction: Hidradenitis suppurativa (HS) is a chronic, inflammatory disorder characterized by painful inflammatory nodules (N), abscesses (A) and draining tunnels (dT), primarily affecting intertriginous areas. Interleukin-36 (IL-36) signaling has been notably expressed within HS inflammatory lesions. To address the need for targeted therapies, this Phase IIa proof-of-clinical-concept (PoCC) study (NCT04762277) explored the effect of spesolimab, an anti-IL-36 receptor monoclonal antibody, in patients with moderate-to-severe HS.&#x0D; Methods: Eligible patients (N=52) were randomized (2:1) to receive spesolimab or placebo (1200 mg intravenous dosing once weekly for three weeks [loading dose], followed by 1200 mg subcutaneous dosing every 2 weeks for 12 weeks). No formal statistical tests were performed, as this was an exploratory study. Of patients who completed the study, 45 were enrolled in an ongoing open-label extension (OLE) study (NCT04876391) with spesolimab. For each study, endpoints included change from baseline at Weeks 12 and 24 in total A, N and dT (ANdT) counts, and adverse events (AEs).&#x0D; Results: Mean changes from baseline at Week 12 in dT, A and total ANdT counts were -1.30, -0.53 and -4.87 in the spesolimab arm, and 1.07, 3.07 and -0.86 in the placebo arm, respectively. Mean changes in N count were numerically similar between the spesolimab (-3.00) and placebo (-5.00) arms. Of patients with ≥1 dT at baseline, a numerically greater proportion had a decrease in dT count at Week 12 in the spesolimab (16/24, 66.7%) versus the placebo (5/13, 38.5%) arm. Least squares mean changes from baseline in total AN count at Week 12 were -38.8% and -34.7% in the spesolimab and placebo arms, respectively, which may have been affected by higher baseline AN and N counts in the spesolimab versus placebo arm. In the OLE, patients originally randomized to spesolimab (n=30) achieved sustained reductions in dT count and in International Hidradenitis Suppurativa Severity Score (IHS4) at Week 24. The safety profile of spesolimab was similar to that reported in other trials; among the 52 patients enrolled in the PoCC study, 77.8% (spesolimab) and 87.5% (placebo) of patients reported ≥1 AE. No patients receiving spesolimab reported serious AEs, and no new safety concerns were identified by Week 24. No deaths were reported.&#x0D; Conclusion: Our findings show that spesolimab was well tolerated and decreased all HS lesions. These results support the development of spesolimab in HS.&#x0D; This study was supported and funded by Boehringer Ingelheim.

Assessment of long-term safety and efficacy of dupilumab in children with asthma (LIBERTY ASTHMA EXCURSION): an open-label extension study

Dupilumab efficacy and safety in children aged 6-11 years with uncontrolled, moderate-to-severe asthma were shown in the VOYAGE study-a 52-week, multinational, multicentre, phase 3 randomised, double-blind, placebo-controlled trial. We aimed to evaluate the long-term safety and efficacy of dupilumab in children with moderate-to-severe asthma who previously participated in the VOYAGE study. 365 of 408 children with moderate-to-severe asthma from VOYAGE enrolled in EXCURSION, a 52 week, open-label extension study conducted at 70 centres across 17 countries. 240 children continued with add-on dupilumab (dosed according to bodyweight: 100 mg for those weighing ≤30 kg and 200 mg for those weighing more than 30 kg at EXCURSION baseline) once every 2 weeks administered by subcutaneous injection (dupilumab/dupilumab group) and 125 children on placebo during VOYAGE initiated dupilumab (100 or 200 mg, according to bodyweight), once every 2 weeks administered by subcutaneous injection (placebo/dupilumab group). Following a protocol amendment, for a subset of children weighing 30 kg or less, the dose was changed to 300 mg once every 4 weeks. The primary endpoint for the open-label extension study was the number and proportion of patients with any treatment-emergent adverse event (TEAE) during the 52-week study period in the overall population (defined as children aged 6-11 years old with moderate-to-severe asthma who previously completed VOYAGE). Statistical analyses were descriptive. This study is registered with ClinicalTrials.gov (NCT03560466; EXCURSION). Children who completed VOYAGE were eligible to enrol in EXCURSION between June 21, 2018 and Aug 18, 2020. During EXCURSION, the safety profile and proportion of patients reporting TEAEs were consistent with those observed during the parent study (VOYAGE). In the overall population, 232 (63·6%) of 365 patients experienced at least one TEAE (dupilumab/dupilumab: 147 [61·3%]; placebo/dupilumab: 85 [68·0%]). The most frequently reported TEAEs were nasopharyngitis, pharyngitis, and upper respiratory tract infections. In EXCURSION, long-term treatment with dupilumab was well tolerated with an acceptable safety profile. Sanofi and Regeneron Pharmaceuticals.

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)

Abstract 14714: Long-Term Neurocognitive Safety of LDL-C Lowering With Evolocumab: Open-Label Extension Data From FOURIER

Background: Concerns have been raised about low LDL-C levels and possible adverse effects on cognition. PCSK9 inhibitors markedly lower LDL-C, yet EBBINGHAUS, a prespecified substudy within the FOURIER trial, did not show adverse cognitive changes with evolocumab over 19 months median follow-up. Purpose: To investigate the long-term effects of evolocumab on cognitive function. Methods: EBBINGHAUS was a substudy of cognitive function using the Cambridge Neuropsychological Test Automated Battery (CANTAB) within the FOURIER randomized trial of evolocumab vs placebo in patients with established ASCVD. Patients in North America and Europe who completed EBBINGHAUS on study drug were eligible for an open-label extension (OLE) study with evolocumab. The primary endpoint was change in spatial working memory strategy index of executive function score (SWMI) from baseline over time. Secondary endpoints were measures of working memory, episodic memory, and psychomotor speed. A paired t-test was used to compare baseline vs post-baseline scores during OLE. Results: Of 1204 patients from EBBINGHAUS, 306 entered the OLE and were treated with evolocumab for a median of 5.1 years. Median achieved LDL-C was 34 mg/dL (IQR 21-50). No significant change in SWMI occurred during the OLE period overall [mean (±SD) change -0.1±2.7, p=0.73] or when stratified by original randomized allocation ( Figure 1A ). For secondary outcomes, one showed no change during the OLE period, two showed small changes (10-15% of SD), but these were directionally inconsistent (one higher, one lower). In 152 patients originally randomized to evolocumab, there was no significant change in SWMI from randomization through long-term follow-up over a median of 6.7 and a maximum of 7.2 years (mean change 0.1±2.6, p=0.66) ( Figure 1B ). Conclusion: Evolocumab did not lead to any apparent long-term decline in cognitive function through follow-up extending up to 7.2 years.

Long-Term Safety and Efficacy of Perfluorohexyloctane Ophthalmic Solution for the Treatment of Patients With Dry Eye Disease: The KALAHARI Study.

The aim of this study was to assess the long-term safety and efficacy of perfluorohexyloctane (PFHO) ophthalmic drop (formerly NOV03) for treatment of dry eye disease (DED). KALAHARI was a phase 3, multicenter, single-arm, open-label extension study in patients aged 18 years or older with DED associated with Meibomian gland dysfunction who completed the randomized, double-masked, hypotonic saline-controlled GOBI study. Patients instilled 1 drop of PFHO (MIEBO, Bausch + Lomb) 4 times daily in both eyes for 52 weeks. Safety assessments included adverse events, best-corrected visual acuity, slit-lamp biomicroscopy, intraocular pressure, and dilated fundoscopy. Efficacy end points included change from GOBI study baseline in total corneal fluorescein staining and eye dryness score (0-100 visual analog scale). Overall, 208 patients from GOBI (PFHO [n = 97]; saline [n = 111]) were rolled over into KALAHARI. Twenty-nine patients (13.9%) had ≥1 ocular adverse event, with most being mild or moderate in severity; the most common ocular adverse events were vitreous detachment (1.9%), allergic conjunctivitis (1.4%), blurred vision (1.4%), and increased lacrimation (1.4%). Other safety end points were unremarkable. For patients continuing PFHO from GOBI, improvements in total corneal fluorescein staining and visual analog scale dryness scores observed in GOBI were maintained throughout KALAHARI. Patients treated with saline in GOBI and switched to PFHO in KALAHARI showed improvements in total corneal fluorescein staining and visual analog scale scores by week 4 that were maintained for the rest of the study. PFHO was safe and well tolerated and maintained efficacy for improving signs and symptoms of DED in this year-long study of patients with DED associated with Meibomian gland dysfunction.

Long-Term Treatment with Fostamatinib in Japanese Patients with Primary Immune Thrombocytopenia: An Open-Label Extension Study Following a Phase 3 Placebo-Controlled, Double-Blind, Parallel-Group Study

Background Fostamatinib, a spleen tyrosine kinase inhibitor, has been approved for the treatment of chronic immune thrombocytopenia (ITP) in adults in the US, Canada, Europe, Israel, and Japan. We evaluated the long-term efficacy and safety of fostamatinib treatment and the off-therapy platelet count in Japanese patients with primary ITP in a phase 3 clinical trial with a 24-week double-blind period, a 28-week open-label extension period, and a pre-defined washout period. Methods The trial enrolled Japanese patients who had failed to respond or did not tolerate ≥1 prior ITP treatment, who had a mean platelet count &amp;lt;30,000/μL (based on 3 screening and baseline platelet measurements), and had a platelet count at each visit &amp;lt;35,000/μL. Dosing was at 100 mg bid for 4 weeks and then 150 mg bid if needed and tolerated. One concomitant treatment was allowed (corticosteroids, azathioprine or danazol). The dosage of the concomitant treatment was to remain the same during the 24-week double-blind period but could be reduced or discontinued during the open-label period. Efficacy endpoints were platelet response rate (i.e., the percentage of patients who achieved a platelet count of ≥ 50 × 10 3/μL at 2 consecutive visits at least 28 days apart). The platelet count of the responders during the study period were evaluated. Results A total of 33 patients who were either treated with fostamatinib in the 24-week double-blind period (Fostamatinib-Fostamatinib group, n=22) or treated with placebo in the double-blind period and then treated with fostamatinib in the 28-week open-label extension period (Placebo-Fostamatinib group, n=11) were analyzed. Of those, 79% (26/33) were women, the median age was 62, the median baseline platelet count was 19 x 10 3/μL, and 58% (19/33) had two or more previous treatments. The platelet response rate was 36% (8/22) in the Fostamatinib-Fostamatinib group and 27% (3/11) in the Placebo-Fostamatinib group. The platelet count of the responders in the Fostamatinib-Fostamatinib group increased to ≥50 × 10 3/μL shortly after initiating fostamatinib and remained around 100 × 10 3/μL between Week 14 and Week 52, whereas the platelet count of the responders in the Placebo-Fostamatinib group remained low while receiving placebo but increased after receiving fostamatinib ( Figure 1). Among 14 patients with concomitant glucocorticoids treatments at the beginning of the open-label period, 43% (6/14) reduced or discontinued glucocorticoids while receiving fostamatinib without disease relapse. In the washout period of up to 4 weeks, all 12 patients experienced a mild decrease in platelet count, but none developed bleeding events ( Figure 2). Three of four patients who completed the 4-week washout period had a slight increase in platelet counts from Week 2 to Week 4. In the double-blind and open-label periods, adverse events were reported in 96% (21/22) of the Fostamatinib-Fostamatinib group and 100% (11/11) of the Placebo-Fostamatinib group, and treatment-related adverse events in 77% (17/22) and 46% (5/11), respectively. In the washout period, adverse events were reported in 50% (6/12) of patients, and treatment-related adverse events in 0% (0/12). We found no new safety risk or late-onset adverse events specific to Japanese patients. Conclusions The long-term efficacy and safety of fostamatinib were observed in Japanese patients with primary ITP, along with the feasibility of glucocorticoid reduction/discontinuation during fostamatinib treatment, and a lack of bleeding events after abrupt discontinuation of fostamatinib. The findings obtained from this study will help position fostamatinib as a second-line treatment in patients with primary ITP.

Over 4 Years of Safety and Efficacy with Voxelotor Treatment for Patients with Sickle Cell Disease: Updated Results from an Open-Label Extension of the Phase 3 HOPE Trial

Introduction: Sickle cell disease (SCD) is an inherited blood disorder caused by a homozygous or compound heterozygous mutation in the hemoglobin (Hb) subunit β gene, leading to sickle hemoglobin (HbS). Polymerization of HbS results in red blood cell sickling/damage and leads to hemolysis, chronic anemia, and vaso-occlusive crises (VOCs). Hemolysis and low Hb put patients with SCD at risk of end-organ damage, increased morbidity, and early mortality. Voxelotor, a first-in-class HbS polymerization inhibitor, is approved in the US for the treatment of patients with SCD aged ≥4 years and in Europe for the treatment of hemolytic anemia due to SCD in patients aged ≥12 years. In the phase 3, randomized, placebo-controlled HOPE trial (NCT03036813), significantly more patients (aged ≥12 years) treated with voxelotor 1500 mg achieved a &amp;gt;1 g/dL Hb increase vs placebo (89% vs 25%, respectively) at any time up to Week 72. Hb increases were associated with reductions in markers of hemolysis (indirect bilirubin, reticulocyte percentage, and lactate dehydrogenase). To assess the safety and efficacy of long-term voxelotor use, we report an updated interim analysis of an open-label extension (OLE) of the HOPE trial. Methods: Patients who completed the HOPE trial were eligible to enroll in the multicenter, global OLE study (NCT03573882) and receive ongoing treatment with once daily voxelotor 1500 mg if they continued to derive clinical benefit and/or until voxelotor was available via an alternative source. Adverse event (AE) data were collected through 28 days after voxelotor discontinuation, and measurements of Hb and clinical markers of hemolysis were summarized through 168 weeks of treatment in the OLE. Central laboratory assessments were used for the US and Europe through Week 48; local laboratory assessments were used for the rest of the world throughout the study. The annualized rate of VOCs was calculated from events reported as sickle cell anemia with crisis or acute chest syndrome. Data presented are based on an interim data cut (Dec 31, 2022). Results: Of 199 patients who completed the HOPE trial, 178 (89.4%) were enrolled and dosed in the OLE. Median age at enrollment was 25 years (15.7% adolescents, 84.3% adults). At data cutoff, the median (range) duration of voxelotor exposure the OLE was 124.0 (1.9-205.9) weeks, and 81 patients were treated for ≥168 weeks. Of these 81 patients, 52 had previously received voxelotor in the randomized part of the study, for a combined duration of exposure of ≥240 weeks (4.6 years). In 17 patients previously treated with placebo who remained on study through 168 weeks, the mean (SD) Hb change from baseline (start of OLE) was 1.1 (1.51) g/dL. The mean (SD) Hb change from baseline for patients who previously received voxelotor 1500 mg was 0.5 (1.49) g/dL (n=18), indicating durability of response. Markers of hemolysis improved from baseline to 168 weeks in patients who received placebo in the HOPE trial (median decreases of 44.3% in indirect bilirubin [n=19] and 52.3% in reticulocyte percentage [n=14]). Patients who received 1500 mg voxelotor in the HOPE trial showed a stable response at Week 168 (median decreases of 25.2% in indirect bilirubin [n=17] and 53.3% in reticulocyte percentage [n=17]). The annualized incidence rate of VOCs was 1.1 (95% CI: 1.0-1.2) events per year across all patients. A total of 157/178 patients (88.2%) reported a non-SCD-related treatment-emergent AE (TEAE); the most commonly reported TEAEs were arthralgia, headache, pain in extremity, and upper respiratory tract infection (Table). Many TEAEs were reported during the COVID-19 pandemic; most were grade 1 or 2 in severity. AEs that led to treatment discontinuation occurred in 16 patients (9.0%). Eight deaths occurred, none deemed related to voxelotor treatment. Conclusions: In this updated analysis from the HOPE OLE,treatment with voxelotor 1500 mg resulted in improvements in Hb and clinical markers of hemolysis at Week 168 in patients who received placebo in the HOPE trial. Treatment with voxelotor 1500 mg showed durability of response in patients who received voxelotor in the HOPE trial. The safety profile in the OLE was consistent with findings from the HOPE trial, and no new safety signals were identified with exposure through a combined 240 weeks of treatment. Long-term use of voxelotor was well tolerated and effective at maintaining reductions in anemia and hemolysis, with a low rate of VOCs, in patients with SCD.

188 Laboratory safety of long-term dupilumab treatment in a 5-year open-label extension study of adults with moderate-to-severe atopic dermatitis

188 Laboratory safety of long-term dupilumab treatment in a 5-year open-label extension study of adults with moderate-to-severe atopic dermatitis