Open-label Extension Baseline Research Articles

Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER

PurposeEvaluate long-term efficacy and safety of elamipretide during the open-label extension (OLE) of the TAZPOWER trial in individuals with Barth syndrome (BTHS). MethodsTAZPOWER was a 28-week randomized, double-blind, and placebo-controlled trial followed by a 168-week OLE. Patients entering the OLE continued elamipretide 40 mg subcutaneous daily. OLE primary endpoints were safety and tolerability; secondary endpoints included change from baseline in the 6-minute walk test (6MWT) and BarTH Syndrome Symptom Assessment (BTHS-SA) Total Fatigue score. Muscle strength, physician- and patient-assessed outcomes, echocardiographic parameters, and biomarkers, including cardiolipin (CL) and monolysocardiolipin (MLCL), were assessed. ResultsTen patients entered the OLE; 8 reached the week 168 visit. Elamipretide was well tolerated, with injection-site reactions being the most common adverse events. Significant improvements from OLE baseline on 6MWT occurred at all OLE time points (cumulative 96.1 m of improvement [week 168, P = .003]). Mean BTHS-SA Total Fatigue scores were below baseline (improved) at all OLE time points. Three-dimensional (3D) left ventricular stroke, end-diastolic, and end-systolic volumes improved, showing significant trends for improvement from baseline to week 168. MLCL/CL values showed improvement, correlating to important clinical outcomes. ConclusionElamipretide was associated with sustained long-term tolerability and efficacy, with improvements in functional assessments and cardiac function in BTHS.

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).

Long-Term Treatment With Sacubitril/Valsartan in Japanese Patients With Chronic Heart Failure and Reduced Ejection Fraction - Open-Label Extension of the PARALLEL-HF Study.

The PARALLEL-HF study assessed the efficacy and safety of sacubitril/valsartan vs. enalapril in Japanese patients with chronic heart failure with reduced ejection fraction (HFrEF). This open-label extension (OLE) assessed long-term safety with sacubitril/valsartan.Methods and Results: This study enrolled 150 patients who received sacubitril/valsartan 50 or 100 mg, b.i.d., in addition to optimal background heart failure (HF) therapy. A dose level of sacubitril/valsartan 200 mg, b.i.d., was targeted by Week 8. At OLE baseline, higher concentrations of B-type natriuretic peptide (BNP) and urine cGMP, and lower concentrations of N-terminal pro B-type natriuretic peptide (NT-proBNP), were observed in the sacubitril/valsartan core group (patients who received sacubitril/valsartan in both the core and extension study) than in the enalapril core group (patients who received enalapril in the core study and were then transitioned to sacubitril/valsartan). The mean exposure to study drug was 98.9%. There was no trend of worsening of HF at Month 12. No obvious changes in cardiac biomarkers were observed, whereas BNP and urine cGMP increased and NT-proBNP decreased in the enalapril core group, which was evident at Weeks 2-4 and sustained to Month 12. Long-term sacubitril/valsartan at doses up to 200 mg, b.i.d., has a positive risk-benefit profile; it was safe and well tolerated in Japanese patients with chronic HFrEF.

Long-term inhaled treprostinil for pulmonary hypertension due to interstitial lung disease: INCREASE open-label extension study.

The 16-week randomised, placebo-controlled INCREASE trial (RCT) met its primary end-point by improving 6-min walk distance (6MWD) in patients receiving inhaled treprostinil for pulmonary hypertension due to interstitial lung disease (PH-ILD). The open-label extension (OLE) evaluated long-term effects of inhaled treprostinil in PH-ILD. Of 258 eligible patients, 242 enrolled in the INCREASE OLE and received inhaled treprostinil. Assessments included 6MWD, pulmonary function testing, N-terminal pro-brain natriuretic peptide (NT-proBNP), quality of life and adverse events. Hospitalisations, exacerbations of underlying lung disease and death were recorded. At INCREASE OLE baseline, patients had a median age of 70 years and a mean 6MWD of 274.2 m; 52.1% were male. For the overall population, the mean 6MWD at week 52 was 279.1 m and the mean change from INCREASE RCT baseline was 3.5 m (22.1 m for the prior inhaled treprostinil arm and -19.5 m for the prior placebo arm); the median NT-proBNP decreased from 389 pg·mL-1 at RCT baseline to 359 pg·mL-1 at week 64; and the absolute (% predicted) mean forced vital capacity change from RCT baseline to week 64 was 51 mL (2.8%). Patients who received inhaled treprostinil versus placebo in the RCT had a 31% lower relative risk of exacerbation of underlying lung disease in the OLE (hazard ratio 0.69 (95% CI 0.49-0.97); p=0.03). Adverse events leading to drug discontinuation occurred in 54 (22.3%) patients. These results support the long-term safety and efficacy of inhaled treprostinil in patients with PH-ILD, and are consistent with the results observed in the INCREASE RCT.

336 Efficacy of dupilumab in infants and preschoolers with atopic dermatitis up to 1 year

Abstract Continuous use of several traditional systemic atopic dermatitis (AD) treatments in pediatric patients is not recommended due to safety concerns and lack of long-term efficacy data. Children aged 6 months to 5 years with moderate-to-severe AD who had participated in the 16-week, double-blind, phase 3 LIBERTY AD PRESCHOOL trial (NCT03346434, part B; parent study) were enrolled in an open-label extension (OLE) study (NCT02612454). Patients received subcutaneous dupilumab every 4 weeks (200 mg for children weighing 5 to <15 kg; 300 mg for 15 to <30 kg). Topical AD treatments were allowed. Relative to the parent study baseline, mean percentage changes (± standard error) in Eczema Area and Severity Index score were −41.6 (±4.6) and −54.0 (±3.2) at OLE baseline, −74.5 (±3.7) and −81.7 (±1.8) at week 16, and −85.6 (±3.5) and −86.4 (±2.2) at week 52 in the 200 and 300 mg dupilumab groups, respectively. The number of patients (%) achieving an Investigator’s Global Assessment score of 0/1 increased from OLE baseline (6/61 [9.8%] and 15/116 [12.9%]) to week 16 (22/58 [37.9%] and 35/115 [30.4%]), and at week 52 (16/34 [47.1%] and 18/54 [33.3%]) in the 200 and 300 mg dupilumab groups, respectively. The overall safety of dupilumab treatment administered for up to 1 year was consistent with the known dupilumab safety profile. Dupilumab treatment for 1 year provides sustained improvement in signs of AD in patients aged 6 months to 5 years with moderate-to-severe AD.

Lipid profile with eslicarbazepine acetate and carbamazepine monotherapy in adult patients with newly diagnosed focal seizures: post hoc analysis of a phase III trial and open-label extension study.

Antiseizure medications can have negative effects on plasma lipid levels. To evaluate plasma lipid changes in patients with newly diagnosed focal epilepsy treated with eslicarbazepine acetate (ESL) or controlled-release carbamazepine (CBZ-CR) monotherapy during a phase III, randomized, double-blind (DB) trial and 2 years of ESL treatment in an open-label extension (OLE). Post hoc analysis of a phase III trial and OLE study. Proportions of patients with elevated levels of total cholesterol and low-density lipoprotein (LDL) cholesterol were assessed at DB baseline, OLE baseline (last visit of DB trial), and end of OLE. A total of 184 patients received ESL monotherapy during the OLE: 96 received ESL monotherapy in the DB trial and 88 patients received CBZ-CR monotherapy. The proportions of patients with elevated total cholesterol and LDL cholesterol increased significantly during the DB trial in those treated with CBZ-CR monotherapy [total cholesterol, +14.9% (p < 0.001); LDL cholesterol, +11.5% (p = 0.012)] but decreased significantly after switching to ESL monotherapy in the OLE [total cholesterol, -15.3% (p = 0.008); LDL cholesterol, -11.1% (p = 0.021)]. No significant changes were observed in those treated with ESL monotherapy during the DB trial and OLE. At the end of the DB trial, between-group differences (ESL-CBZ-CR) in the proportions of patients with elevated total and LDL cholesterol were -13.6% (p = 0.037) and -12.3% (p = 0.061), respectively; at the end of the OLE, these between-group differences were -6.0% (p = 0.360) and -0.6% (p = 1.000), respectively. A lower proportion of patients with newly diagnosed focal epilepsy had increased levels of total and LDL cholesterol, compared to baseline, following monotherapy with ESL versus CBZ-CR; after switching from CBZ-CR to ESL, the proportions of patients with increased levels decreased significantly. ClinicalTrials.gov NCT01162460/NCT02484001; EudraCT 2009-011135-13/2015-001243-36.

Lecanemab in patients with early Alzheimer’s disease: detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study

BackgroundLecanemab, a humanized IgG1 monoclonal antibody that targets soluble aggregated Aβ species (protofibrils), has demonstrated robust brain fibrillar amyloid reduction and slowing of clinical decline in early AD. The objective of this analysis is to report results from study 201 blinded period (core), the open-label extension (OLE), and gap period (between core and OLE) supporting the effectiveness of lecanemab.MethodsThe lecanemab study 201 core was a double-blind, randomized, placebo-controlled study of 856 patients randomized to one of five dose regimens or placebo. An OLE of study 201 was initiated to allow patients to receive open-label lecanemab 10mg/kg biweekly for up to 24 months, with an intervening off-treatment period (gap period) ranging from 9 to 59 months (mean 24 months).ResultsAt 12 and 18 months of treatment in the core, lecanemab 10 mg/kg biweekly demonstrated dose-dependent reductions of brain amyloid measured PET and corresponding changes in plasma biomarkers and slowing of cognitive decline. The rates of clinical progression during the gap were similar in lecanemab and placebo subjects, with clinical treatment differences maintained after discontinued dosing over an average of 24 months in the gap period. During the gap, plasma Aβ42/40 ratio and p-tau181 levels began to return towards pre-randomization levels more quickly than amyloid PET. At OLE baseline, treatment differences vs placebo at 18 months in the randomized period were maintained across 3 clinical assessments. In the OLE, lecanemab 10 mg/kg biweekly treatment produced dose-dependent reductions in amyloid PET SUVr, improvements in plasma Aβ42/40 ratio, and reductions in plasma p-tau181.ConclusionsLecanemab treatment resulted in significant reduction in amyloid plaques and a slowing of clinical decline. Data indicate that rapid and pronounced amyloid reduction correlates with clinical benefit and potential disease-modifying effects, as well as the potential to use plasma biomarkers to monitor for lecanemab treatment effects.Trial registrationClinicalTrials.gov NCT01767311.

EFFICACY OF DUPILUMAB IN INFANTS AND PRESCHOOLERS WITH ATOPIC DERMATITIS UP TO 1 YEAR

<h3>Introduction</h3> Continuous use of several traditional systemic atopic dermatitis (AD) treatments in pediatric patients is not recommended due to safety concerns and lack of long-term efficacy data. <h3>Methods</h3> Children aged 6 months to 5 years with moderate-to-severe AD who had participated in the 16-week, double-blind, phase 3 LIBERTY AD PRESCHOOL trial (NCT03346434, part B; parent study) were enrolled into an open-label extension (OLE) study (NCT02612454). Patients received subcutaneous dupilumab every 4 weeks (200mg for children weighing 5 to <15kg; 300mg for 15 to <30kg). Topical AD treatments were allowed. <h3>Results</h3> Relative to parent study baseline, mean percentage changes (± standard error) in Eczema Area and Severity Index score were −41.6 (±4.6) and −54.0 (±3.2) at OLE baseline, −74.5 (±3.7) and −81.7 (±1.8) at Week 16, and −85.6 (±3.5) and −86.4 (±2.2) at Week 52 in the 200mg and 300mg dupilumab groups, respectively. The number of patients (%) achieving an Investigator's Global Assessment score of 0/1 increased from OLE baseline (6/61 [9.8%] and 15/116 [12.9%]), to Week 16 (22/58 [37.9%] and 35/115 [30.4%]), and at Week 52 (16/34 [47.1%] and 18/54 [33.3%]) in the 200mg and 300mg dupilumab groups, respectively. Overall safety of dupilumab treatment administered for up to 1 year was consistent with the known dupilumab safety profile. <h3>Conclusion</h3> Dupilumab treatment for 1 year provides sustained improvement in signs of AD in patients aged 6 months to 5 years with moderate-to-severe AD.

LBMON178 2nd Year Outcomes Of The Open-label Extension Of Chiasma Optimal, A Phase 3 Study Of Oral Octreotide Capsules In Acromegaly

Abstract Background Oral octreotide capsules (OOC) are an approved treatment option in the United States for patients with acromegaly who have previously responded to injectable somatostatin receptor ligands (iSRLs). Safety and efficacy of OOC was demonstrated in the CHIASMA OPTIMAL trial (NCT03252353), showing maintenance of response and a safety profile consistent with iSRLs. Results from the first 48 weeks of the open-label extension (OLE) of this trial suggested that this effect was durable for the long-term. Objective Report efficacy and safety through the second year of the OLE. Methods Eligible patients had the option to enroll in the OLE of CHIASMA OPTIMAL following the double-blind placebo-controlled (DPC) period. Endpoints in the second year of the OLE were exploratory, including: the proportion of patients completing week 96 of the OLE, the proportion of responders entering year 2 who remained responders of those with evaluable data (response defined as average Insulin-like growth factor I [IGF-I] ≤1. 0 × upper limit of normal [ULN] at last 2 visits between weeks 84-96), and changes in IGF-I and growth hormone (GH) from OLE baseline to OLE week 96 in those completing the DPC period on study drug. Results Thirty-two patients from the core period (DPC groups: n=14, placebo; n=18, OOC) entered year 2 of the OLE and 31 (97%) completed. OOC dose at the start of year 2 was 40 mg/d, n=3; 60 mg/d, n=8; and 80 mg/d, n=21. For patients who had non-missing data response rate at 96 weeks was 100% (17/17) for patients who entered year 2 as responders, and 93% (27/29) for patients overall. Mean IGF-I for patients from the OOC group who completed the DPC period on study drug (n=14) was 0.81 × ULN at baseline of OLE and 0.78 × ULN at week 96, (change, −0. 03 × ULN). Mean GH (n=12) was 0.43 ng/mL and 0.44 ng/mL at baseline and week 96, respectively (change, 0. 01 ng/mL). For patients who completed the DPC period on placebo (n=8), mean IGF-I was 1. 05 and 0.77 × ULN at OLE baseline and week 96, respectively (change, −0.28); mean GH (n=5) was 1. 06 and 0.34 ng/mL at OLE baseline and week 96, respectively (change, −0.72 ng/mL). Median exposure to OOC was 2.1 years, with exposure &amp;gt;3 years for 5 patients. Throughout the OLE period, 50% of patients experienced adverse events (AEs), with no serious AEs. One patient discontinued treatment due to an AE (headache). The safety profile was consistent with that reported for OOC; no new patterns were observed with increased exposure. Conclusion Maintenance of biochemical response with OOC was durable up to 96 weeks. The safety profile of OOC was consistent with that of iSRLs. No new safety signals were observed with increased exposure duration. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Safety and Sustained Efficacy of the Farnesoid X Receptor (FXR) Agonist Cilofexor Over a 96-Week Open-label Extension in Patients With PSC

Primary sclerosing cholangitis (PSC) is a major unmet medical need in clinical hepatology. Cilofexor is a nonsteroidal farnesoid X receptor agonist being evaluated for the treatment of PSC. Here, we describe the safety and preliminary efficacy of cilofexor in a 96-week, open-label extension (OLE) of a phase II trial. Noncirrhotic subjects with large-duct PSC who completed the 12-week, blinded phase of a phase II study (NCT02943460) were eligible, after a 4-week washout period, for a 96-week OLE with cilofexor 100 mg daily. Safety, liver biochemistry, and serum markers of fibrosis, cellular injury, and pharmacodynamic effects of cilofexor (fibroblast growth factor 19, C4, and bile acids [BAs]) were evaluated. Among 52 subjects enrolled in the phase II study, 47 (90%) continued in the OLE phase (median age, 44 years; 60% male patients, 60% with inflammatory bowel disease, and 45% on ursodeoxycholic acid [UDCA]). At OLE baseline (BL), the median serum alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) were 368 U/L (interquartile range [IQR], 277-468 U/L) and 417 U/L (IQR, 196-801 U/L), respectively. Of the 47 subjects enrolled, 15 (32%) discontinued treatment prematurely (pruritus [n= 5], other adverse events [n= 5], subject decision/investigator discretion [n= 5]). At week 96, reductions in liver biochemistry parameters occurred, including serum ALP (median,-8.3% [IQR,-25.9% to 11.0%]; P= .066), GGT (-29.8% [IQR,-42.3% to-13.9%]; P < .001), alanine aminotransaminase (ALT) (-29.8% [IQR,-43.7% to-6.6%]; P= .002), and aspartate aminotransaminase (AST) (-16.7% [IQR,-35.3% to 1.0%]; P= .010), and rebounded after 4 weeks of untreated follow-up. ALP response (≥20% reduction from BL to week 96) was similar in the presence or absence of UDCA therapy (29% vs 39%; P= .71). At week 96, cilofexor treatment was associated with a significant reduction in serum 7α-hydroxy-4-cholesten-3-one (C4) (-29.8% [IQR,-64.3% to-8.5%]; P= .001). In subjects with detectable serum BAs at BL (n= 40), BAs decreased-23.9% (IQR,-44.4% to-0.6%; P= .006) at week 48 (n= 28) and-25.7% (IQR,-35.9% to 53.7%; P= .91) at week 96 (n= 26). Serum cytokeratin 18 (CK18) M30 and M65 were reduced throughout the OLE; significant reductions were observed at week 72 (CK18 M30,-17.3% [IQR,-39.3% to 8.8%]; P= .018; CK18 M65,-43.5% [IQR,-54.9% to 15.3%]; P= .096). At week 96, a small, but statistically significant absolute increase of 0.15 units inEnhanced Liver Fibrosis score was observed compared with BL (median, 9.34 vs 9.53; P=.028). In this 96-week OLE of a phase II study of PSC, cilofexor was safe and improved liver biochemistry and biomarkers of cholestasis and cellular injury. gov identifier: NCT02943460.

Effect of less aggressive treatment on diabetic retinopathy severity scale scores: analyses of the RIDE and RISE open-label extension

ObjectiveTo evaluate factors associated with Diabetic Retinopathy Severity Scale (DRSS) changes with less frequent ranibizumab after induction therapy.Methods and analysisPost hoc analyses of RIDE/RISE and their open-label extension (OLE). Analyses...

Efficacy and safety of dupilumab in children aged 6–11 years with inadequately controlled severe atopic dermatitis: Results from an open-label extension trial up to 1 year

Introduction (contexte de la recherche) Atopic dermatitis (AD), a common chronic inflammatory type 2 systemic disease, is characterized by pruritus, disruption of skin barrier function and eczematous lesions. Treatment options are limited, especially for children. To report long-term efficacy and safety of dupilumab in patients (pts) aged 6–11 years with severe AD from the open-label extension (OLE) study ( NCT02612454 ). Children (6–11 years) with severe AD from the 16-week (wk), double-blind, phase 3 LIBERTY AD PEDS study ( NCT03345914 ; parent study) enrolled in the long-term, multicentre OLE study and were treated with 300 mg dupilumab every 4 wks. If treatment response was inadequate (failure to achieve Investigator's Global Assessment [IGA] score of 0/1 within 16 wks) it could be up-titrated to 200 mg/300 mg every 2 wks (< 60 kg/ ≥ 60 kg, respectively). Concomitant topical treatments were permitted. Data are as observed. In the OLE, pts ( n = 321) had a mean (standard deviation [SD]) age of 8.6 (1.7) years and AD duration of 7.4 (2.2) years. Mean percentage change (SD) from parent study baseline (PSBL) to OLE baseline (BL) in Eczema Area and Severity Index (EASI) was −62.5 (34.4). In the OLE, mean percentage change from PSBL in EASI improved at Wk 16 (−79.6 [20.8]) and Wk 52 (−86.0 [13.9]). Relative to PSBL, the proportion of pts achieving ≥ 50% and ≥ 75% reduction in EASI increased from OLE BL (EASI-50: 230/321 [71.7%]; EASI-75: 142/321 [44.2%]) to OLE Wk 52 (EASI-50: 250/257 [97.3%]; EASI-75: 210/257 [81.7%]). The proportion of pts achieving IGA 0/1 increased from OLE BL (62/321 [19.3%]) to Wk 52 (104/257 [40.5%]). 255 (79.4%) pts reported ≥ 1 treatment-emergent adverse events (TEAEs). Most common TEAEs were dermatitis atopic (28.7%), nasopharyngitis (17.1%) and upper respiratory tract infection (15.6%). 15 (4.7%) and 13 (4.0%) pts reported serious and severe TEAEs, respectively. Dupilumab treatment resulted in substantial and sustained long-term reduction in AD signs and symptoms in pts aged 6–11 years with inadequately controlled severe AD. Long-term safety was acceptable and consistent with that previously seen in shorter term, placebo-controlled studies.

Long-term Effect of Denosumab on Bone Microarchitecture as Assessed by Tissue Thickness-Adjusted Trabecular Bone Score (TBS) in Postmenopausal Women with Osteoporosis: Results from the Freedom and Open-Label Extension (OLE)

TBS is an indirect measure of bone microarchitecture assessed on lumbar spine (LS) DXA scans and provides information beyond bone mineral density (BMD). TBS algorithm has been updated to account for regional soft tissue noise in DXA images. This retrospective analysis applied updated built-in tissue thickness-adjusted TBS algorithm to investigate the long-term effect of denosumab on bone microarchitecture in FREEDOM and OLE. This analysis included 279 postmenopausal women with LS or total hip BMD T-score <−2.5 and ≥−4.0 who completed the FREEDOM DXA sub study and continued in the OLE study: 150 women received denosumab 60 mg subcutaneously every 6 months for 3 years and same-dose open-label denosumab for 7 years (long-term denosumab group); 129 women received placebo for 3 years and open-label denosumab for 7 years (crossover denosumab group). BMD and TBS were assessed on LS DXA scans, blinded from treatment allocation, at FREEDOM: baseline, Month 1, and Years 1, 2, and 3; and at OLE: baseline, Years 1, 2, 3, 5, and 7. Baseline characteristics were similar between groups. Long-term denosumab led to significant and progressive increases in TBS over 10 years of treatment (Figure). A similar trend was observed in the crossover group during 7 years of denosumab therapy. In the long-term denosumab group, % of patients with normal microarchitecture (TBS >1.074) increased from 26.1% at baseline to 53.2% up to Year 10, and % of patients with degraded (TBS ≤1.027) or partially degraded (1.027< TBS≤1.074) microarchitecture decreased from 48.6% to 29.1% and from 25.4% to 17.7%, respectively (P < 0.0001; TBS thresholds equivalent to 1.230 and 1.310 for the classical TBS algorithm corrected for body mass index). A similar improvement in bone microarchitecture was observed in the crossover group from OLE baseline up to OLE Year 7 (P < 0.0001). Over the course of long-term denosumab treatment, TBS changes were largely unrelated to LS BMD changes: r2 was 0.05 from baseline to Year 10 in the long-term group and 0.28 from OLE baseline to OLE Year 7 in the crossover group. Up to 10 years of denosumab treatment significantly and progressively improved TBS assessment of bone microarchitecture independently of BMD in postmenopausal women with osteoporosis.

Exploring steroid tapering in patients with neuromyelitis optica spectrum disorder treated with satralizumab in SAkuraSky: A case series

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) is a rare, chronic, autoimmune disease, characterized by astrocytopathic lesions in the central nervous system (Beekman et al., 2019; Fujihara et al., 2020). The main aim of NMOSD maintenance therapy is to reduce the frequency and severity of relapses and minimize future disability (Fujihara et al., 2020). Oral corticosteroids are used long-term to prevent relapses, but are associated with serious complications (Kessler et al., 2016; Kimbrough et al., 2012). In the SAkuraSky study, satralizumab reduced the risk of relapse in patients with NMOSD compared with placebo, with comparable rates of serious adverse events and infections between treatment arms (Yamamura et al., 2019). Here, we report on 16 patients who tapered their steroid dose during the openlabel extension (OLE) period of SAkuraSky. MethodsSAkuraSky was a phase 3, multicenter, randomized, double-blind (DB), placebo-controlled study of satralizumab in combination with immunosuppressive therapies (ISTs) in patients with NMOSD. Patients were randomized 1:1 to receive 120 mg subcutaneous satralizumab or placebo in addition to a stable dose of their baseline IST. After completing the DB period or experiencing relapse, patients could enter the OLE period. In the OLE, all patients received satralizumab, and IST doses could be tapered at the investigator’s discretion. We assessed the different steroid tapering patterns and their impact on relapse and safety. Patients were considered to have tapered their steroids if their steroid dose at the clinical cut-off date (CCOD: February 18, 2020) was lower than on the first day of the OLE. Annualized relapse rate (ARR) was calculated as the number of relapses divided by the total number of patientyears at risk. ResultsOverall, 36 patients receiving oral corticosteroids entered the OLE, of whom 16 tapered their steroid dose. The mean age (range) at baseline was 44.9 (16–73) years, all 16 were female, 14 (88%) were Japanese, and 15 (94%) were AQP4-IgG seropositive. None were receiving any additional ISTs. Patients tapered their steroids from a median of 10 (range: 5–25) mg/day at OLE baseline to 2.75 (0–15) mg/day at the CCOD. Three patients discontinued steroids entirely, and all three remained relapse free. One patient who remained relapse free had temporary increases in steroid dose. Three relapses were observed in two patients who tapered steroids during the OLE; all three relapses required treatment. One of the relapses occurred shortly after a drop in steroid dose from 25 to 10 mg/day. The ARR for steroid-tapered patients was numerically lower in the OLE period than the satralizumab group in the DB period. The safety profile of satralizumab was in line with the overall SAkuraSky population. Two serious infections were observed in steroid-tapered patients in the OLE, both in the same patient: one event (hepatitis E) occurred before the patient began tapering their steroid dose; and one event (influenza) occurred while the patient was tapering. ConclusionDuring the OLE of SAkuraSky, 16 patients tapered steroids and the ARR did not increase from the DB period. Patient numbers limit interpretation.

Preliminary assessment of the clinical effects of lecanemab following 18 months of treatment in the open label extension of the phase 2 proof of concept study, BAN2401‐G000‐201, in subjects with early Alzheimer’s disease

AbstractBackgroundLecanemab (BAN2401) is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (oligomers, protofibrils) and insoluble fibrils. Lecanemab reduced amyloid and slowed clinical decline in an 18‐month Phase 2 proof of concept study in early Alzheimer’s disease (Alz Res Therapy 13; 2021). An Open label extension (OLE) with 10 mg/kg IV biweekly lecanemab dosing was implemented after analysis of the Core study, with an intervening gap period off‐treatment ranging from 9‐54 months (mean 24 months). The present study assesses longitudinal clinical status (CDR‐SB, ADAS‐cog, ADCOMS) for subjects completing the Core and 18 months of treatment in OLE.MethodAt entry into the core study, subjects were required to have early AD (amyloid positive) with global CDR of 0.5 or 1. MMRM analyses modeled clinical scales across the Core, variable gap period off lecanemab, and the OLE period. Analyses were stratified based on subjects who were: (1) global CDR ≤1 at OLE baseline; or (2) who had progressed beyond the early AD stage to CDR global &gt;1 by OLE baseline.ResultIn subjects with global CDR ≤1 at OLE baseline, lecanemab treatment differences relative to placebo observed after 18 months of treatment in the Core were maintained at a 3 month (off drug) follow‐up visit and at the end of the gap period (OLE baseline). In the gap period, the rates of progression were similar between those treated with lecanemab and placebo in the core period. Clinical progression in the OLE appeared to plateau with lecanemab treatment among those who were global CDR ≤1 at the OLE baseline, while those who were global CDR &gt;1 continued to progress.ConclusionClinical data from the gap period suggest that subjects may need continued treatment with lecanemab, even though amyloid PET and plasma biomarker findings indicate amyloid has been removed. Apparent differences in clinical progression between those with global CDR ≤1 and those with global CDR &gt;1 suggest the hypothesis that early AD subjects may be more likely to benefit from treatment. These concepts will be further explored in ongoing Phase 3 lecanemab clinical trials.

Plasma Aβ 42:40 ratio tracks with changes in brain amyloid PET SUVr in the core and open label extension of the phase 2 proof of concept study ban2401‐g000‐201 following treatment with lecanemab in subjects with early Alzheimer’s disease

AbstractBackgroundLecanemab (BAN2401) is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species (oligomers, protofibrils) and insoluble fibrils. Lecanemab reduced the amyloid PET standard uptake value ratio (SUVr) and slowed clinical decline in an 18‐month Phase 2 proof of concept study in early Alzheimer’s disease (Alz Res Therapy 13; 2021). An Open label extension (OLE) with 10 mg/kg IV biweekly lecanemab dosing was implemented after analysis of the Core study, with an intervening gap period off‐treatment ranging from 9‐54 months (mean 24 months). The present study aimed to evaluate longitudinal plasma Aβ 42:40 ratio (C2N PrecivityAD assay) and the relationship to longitudinal amyloid PET in the Core study, gap period, and OLE.MethodThe amyloid PET sub‐study in the Core study assessed baseline, 12 months and 18 months SUVr with florbetapir, and participants in the OLE amyloid PET sub‐study were imaged at baseline, 3 or 6 months, and 12 months. Plasma samples were collected at the same timepoints and analyzed as described previously (West et al, Mol Neurodegen 2021). Mean changes from Core or OLE baseline and Pearson correlation coefficients were calculated at the group and individual levels for amyloid PET SUVr and plasma Aβ 42:40 ratio, accounting for repeated measures.ResultOLE subjects with plasma samples (N=121) were evaluated for this analysis. Lecanemab produced dose dependent reductions in PET SUVr, with corresponding increases in plasma Aβ 42:40 ratio in Core and OLE. In the OLE, reductions in PET SUVr were dependent on OLE baseline SUVr; PET reductions in the OLE were inversely correlated with increases in plasma Aβ 42:40 ratio. Changes in plasma Aβ 42:40 ratio were inversely correlated with changes in PET SUVr at the group and individual levels in the Core (group: r=‐0.939, p=0.0056; individual: r=‐0.49; p&lt;0.0001) and OLE (group: r=‐0.907, p=0.0007; individual: r=‐0.31 p=0.0012) studies.ConclusionLecanemab dose‐dependent reduction in brain amyloid PET SUVr correlate with increases in plasma Aβ 42:40 ratio. These data align with the OLE clinical data and suggest that plasma Aβ 42:40 ratio has the potential to track the anti‐amyloid effects of lecanemab in AD patients.

Early Data on Long-term Impact of Inotersen on Quality-of-Life in Patients with Hereditary Transthyretin Amyloidosis Polyneuropathy: Open-Label Extension of NEURO-TTR

IntroductionPatients with hereditary transthyretin amyloidosis associated with polyneuropathy (ATTRv-PN) experience deterioration in health-related quality of life (HRQOL) as the disease progresses. Findings from the randomized placebo-controlled phase III NEURO-TTR study showed treatment benefit of inotersen, an antisense oligonucleotide, for preserving or improving HRQOL after 65 weeks of treatment. The current analysis examines longitudinal trends in specific aspects of HRQOL, including polyneuropathy symptoms, daily activities, and physical, role, and social functioning in patients with ATTRv-PN receiving long-term treatment in a follow-up open-label extension (OLE) study.MethodsOne-hundred thirty-five patients with ATTRv-PN were enrolled in an ongoing 5-year OLE study following completion of NEURO-TTR. Eighty-five patients received continuous weekly treatment with inotersen in both studies (inotersen-inotersen group), while 50 patients switched from placebo to inotersen at OLE study baseline (placebo-inotersen group). Descriptive analyses of changes in domain scores and item responses through week 104 of the OLE study were conducted for measures of neuropathy-related and generic HRQOL: Norfolk QOL-Diabetic Neuropathy (DN) questionnaire and SF-36v2® Health Survey (SF-36v2), respectively.ResultsFor both inotersen-inotersen and placebo-inotersen groups, all Norfolk QOL-DN and most SF-36v2 domain scores remained stable from OLE baseline through week 104. Differences in HRQOL between the two groups at OLE baseline were sustained through week 104. Analysis of item responses from NEURO-TTR baseline to OLE study week 104 (170 weeks) for the inotersen-inotersen group found no notable increases in the proportion of patients reporting substantial impairments across a wide variety of symptoms, daily activities, and functioning.ConclusionLong-term treatment with inotersen preserved HRQOL for patients with ATTRv-PN for periods of up to 3 years. The gap in HRQOL between those who had previously received inotersen or placebo in NEURO-TTR did not close by week 104 of the OLE phase, indicating the importance of early treatment for maintaining HRQOL in these patients.Trial RegistrationClinicalTrials.gov Identifiers NCT01737398 for NEURO-TTR study; NCT02175004 for OLE studyInfographic

Treatment with fenfluramine in patients with Dravet syndrome has no long-term effects on weight and growth

ObjectiveAppetite disturbance and growth abnormalities are commonly reported in children with Dravet syndrome (DS). Fenfluramine (Fintepla) has demonstrated profound reduction in convulsive seizure frequency in DS and was recently approved for use in DS in the US and EU. Prior to its use in epilepsy, fenfluramine was approved to suppress appetite in obese adults. Here, we evaluated the impact of fenfluramine on weight and growth in patients with DS treated for ≥12 months or ≥24 months and compared the results with growth curves in normative reference populations and published historical controls among patients with DS. MethodsHistorical control data from a recent study of 68 patients with DS show decreases in height and weight Z-scores of ∼0.1 standard deviation (SD) for every 12-month increase in age (Eschbach K. Seizure. 2017;52:117–22). Anthropometric data for fenfluramine were extracted from an open-label extension (OLE) study of eligible patients with DS (2–18 y/o; fenfluramine dose: 0.2–0.7 mg/kg/day). Z-score analyses were based on the Boston Children’s Hospital algorithm and assessed potential impact of fenfluramine on growth at OLE baseline, at Month 12, and at Month 24. A mixed-effect model for repeated measures (MMRM) estimated changes in height and weight over time. Height and weight Z-scores were also analyzed by dose group (0.2–<0.3 mg/kg/day, 0.3–<0.5 mg/kg/day, and 0.5–0.7 mg/kg/day), averaged over time. ResultsAt the time of analysis, 279 patients were treated with fenfluramine for ≥12 months; 128 were treated for ≥24 months. Relative to the reference population with DS, fenfluramine treatment for ≥12 months or for ≥24 months had minimal impact on height or weight over time as assessed by Z-score analyses. No substantial dose-dependent changes from baseline were observed at Month 12 nor at Month 24. MMRM showed that patients treated with fenfluramine for ≥12 months (N = 262) had an estimated change in Z-score per year of −0.056 for height and −0.166 for weight. For patients with data from all three time points (baseline, 12 months, and 24 months; N = 110), estimated changes in Z-scores per year were −0.025 for height and −0.188 for weight. MMRM projections based on normative reference growth curves were comparable to growth data from historical control populations with DS. Significance/ConclusionLong-term treatment with fenfluramine had minimal impact on the growth of patients with DS as demonstrated by differences in Z-scores for height and weight at 12 months and at 24 months. Changes in Z-scores for height and weight were consistent with published reports on patients with DS.

One-Year Outcomes of the Open-Label Extension of CHIASMA OPTIMAL, a Phase 3 Study of Oral Octreotide Capsules in Acromegaly

Background: Based on the CHIASMA OPTIMAL study, oral octreotide capsules (OOC) were recently approved in the US as a long-term maintenance therapy for patients with acromegaly previously responding to injectable octreotide or lanreotide, somatostatin receptor ligands (SRLs). Results on longer-term efficacy and safety of OOC from the first 48 weeks of the open-label extension (OLE) of this study are presented here. Methods: Eligible patients had the option to enroll in the OLE of CHIASMA OPTIMAL following the double-blind placebo-controlled (DPC) period; 90% of patients who received OOC in the DPC period enrolled. All patients entering the OLE were initiated on a 60 mg/day dose of OOC and titrated up or down based on insulin-like growth factor I (IGF-I) level and/or acromegaly signs or symptoms. End points in the OLE were exploratory and included the proportion of patients who completed week 48 of the OLE, the proportion who completed as responders (defined as average IGF-I ≤1.0 × upper limit of normal [ULN] at weeks 46/48), and changes in IGF-I from baseline of DPC and OLE until week 48 of the OLE; multiple imputation (MI) was used for missing data. Results: Forty patients entered the OLE (n=20 each; OOC and placebo). Median exposure to OOC in the OLE was > 1 year for those who had been on placebo in the DPC and ≤ 21 months for those who had been on OOC. Dosing of OOC at the end of their participation in the OLE was 40 mg, n=3; 60 mg, n=10; and 80 mg, n=27. In those who received OOC during the DPC, 90% (n=18) completed 48 weeks of the OLE. Of responders at the end of the DPC period (n=14), 92.6% maintained response at OLE week 48. In patients from the OOC group who completed the DPC on study drug, average IGF-I using MI was 0.91 and 0.90 × ULN at OLE baseline and week 48, respectively. The mean change in IGF-I from the baseline of the DPC to OLE week 48 was 0.06 × ULN in patients who completed the DPC on OOC (n=19). In those who received placebo during the DPC, 70% (n=14) completed 48 weeks of the OLE. Of responders at the end of the DPC (n=5), 100% maintained response at OLE week 48. In patients from the placebo group who completed the DPC and did not revert to prior injectable therapy (n=9), the average IGF-I values were 1.09 and 0.87 × ULN at OLE baseline and week 48 respectively, using MI. The mean change in IGF-I from the baseline of the DPC to OLE week 48 was 0.08 × ULN in patients who completed the DPC on placebo (n=9). The most common treatment-emergent adverse events (TEAEs) were gastrointestinal; most were mild or moderate. The incidence of TEAEs was similar between patients who were on OOC or placebo during the DPC. The safety profile during the OLE did not show new concerns with increased duration of drug exposure. Conclusion: Long term maintenance of biochemical response to OOC is durable as assessed following ≤ 21 months of treatment. The OOC safety profile in the extension study is consistent with that of injectable SRLs but without injection-related AEs.

Efficacy results of pimavanserin from a multi-center, open-label extension study in Parkinson's disease psychosis patients

IntroductionPimavanserin, a selective 5-HT2A inverse agonist/antagonist, was approved for hallucinations and delusions associated with Parkinson's disease psychosis (PDP). We present durability of response with pimavanserin in patients with PDP for an additional 4 weeks of treatment. MethodsThis was an open-label extension (OLE) study in patients previously completing one of three double-blind, placebo-controlled (Core) studies. All patients received pimavanserin 34 mg once daily. Efficacy assessments included the Scale for the Assessment of Positive Symptoms (SAPS) PD and H + D scales, Clinical Global Impression (CGI) Improvement and Severity scales and Caregiver Burden Scale (CBS), through 4 weeks in the OLE. Safety assessments were conducted at each visit. ResultsOf 459 patients, 424 (92.4%) had a Week 4 efficacy assessment. At Week 4 (10 weeks total treatment), SAPS-PD mean (standard deviation) change from OLE baseline was −1.8 (5.5) and for SAPS-H + D was −2.1 (6.2) with pimavanserin 34 mg. Patients receiving placebo during the Core studies had greater improvements (SAPS-PD -2.9 [5.6]; SAPS-H + D −3.5 [6.3]) during the OLE. For participants treated with pimavanserin 8.5 or 17 mg during the Core studies, further improvement was observed during the OLE with pimavanserin 34 mg. The mean change from Core Study baseline for SAPS-PD score was similar among prior pimavanserin 34 mg and prior placebo-treated participants (−7.1 vs. −7.0). The CGI-I response rate (score of 1 or 2) at Week 4 was 51.4%. Adverse events were reported by 215 (46.8%) patients during the first 4 weeks of OLE. The most common AEs were fall (5.9%), hallucination (3.7%), urinary tract infection (2.8%), insomnia (2.4%), and peripheral edema (2.2%) ConclusionsPatients previously on pimavanserin 34 mg during three blinded core studies had durability of efficacy during the subsequent 4 week OLE SAPS-PD assessment. Patients previously on blinded placebo improved after 4 weeks of OL pimavanserin treatment. These results in over 400 patients from 14 countries support the efficacy of pimavanserin for treating PDP.