Open-label Extension Treatment Research Articles

Methodology of the SORENTO clinical trial: a prospective, randomised, active-controlled phase 3 trial assessing the efficacy and safety of high exposure octreotide subcutaneous depot (CAM2029) in patients with GEP-NET

BackgroundThe current standard of care (SoC) for the initial treatment of unresectable or metastatic well-differentiated gastroenteropancreatic neuroendocrine tumours (GEP-NET) requires initiation of first-generation somatostatin receptor ligand (SRL) therapy, octreotide and lanreotide, which provide safe and efficacious tumour/symptom control in most patients. However, disease progression can occur with SoC SRL treatment and the optimal dose response of SRL remains unknown. Octreotide subcutaneous depot (CAM2029) is a novel, long-acting, high-exposure formulation that has shown greater bioavailability and improved administration than octreotide long-acting release (LAR) with a well-tolerated safety profile. Retrospective data have highlighted a potential benefit of high-exposure SRL for improved disease control in patients who did not adequately respond to the current SoC SRL treatment. This trial will investigate the efficacy and tolerability of CAM2029 compared to the current SoC, including octreotide LAR and lanreotide autogel (ATG).MethodsSORENTO is a prospective, multicentre, randomised, active-controlled, open-label phase 3 trial aiming to demonstrate superiority of treatment with 20 mg octreotide subcutaneous depot (CAM2029) every 2 weeks (Q2W) compared to treatment with the Investigator’s choice of SRL therapy at standard doses for tumour control (octreotide LAR 30 mg or lanreotide ATG 120 mg every 4 weeks [Q4W]) as assessed by progression-free survival (PFS) in approximately 300 patients with unresectable/metastatic and well-differentiated GEP-NET. Upon confirmation of disease progression (determined by a Blinded Independent Review Committee [BIRC] and defined as per RECIST 1.1), patients may enter an open-label extension treatment period with once weekly dosing, to investigate the effects of higher frequency dosing. Overall survival follow-up will end a maximum of 2 years after primary analysis. The primary endpoint will be analysed after 194 confirmed PFS events.DiscussionThis is the first trial investigating the efficacy of CAM2029 versus SoC SRL therapy using a head-to-head, superiority trial design. It is expected to be the first trial to investigate the efficacy of increased dosing frequency of a high-exposure SRL. A BIRC will limit bias and measurement variability and ensure high-quality efficacy data. Additionally, inclusion of patients with well-differentiated Grade 3 NET may elucidate treatment strategies for this rarely investigated patient population.Trial registrationClinicalTrials.gov NCT05050942. Registered on 21st September 2021.

Evolocumab in paediatric heterozygous familial hypercholesterolaemia: cognitive function during 80 weeks of open-label extension treatment.

PCSK9 inhibition intensively lowers low density lipoprotein cholesterol and is well tolerated in adults and paediatric patients with familial hypercholesterolaemia (FH). HAUSER-RCT showed that 24 weeks of treatment with evolocumab in paediatric patients did not affect cognitive function. This study determined the effects of 80 additional weeks of evolocumab treatment on cognitive function in paediatric patients with heterozygous FH. HAUSER-OLE was an 80-week open-label extension of HAUSER-RCT, a randomized, double-blind, 24-week trial evaluating the efficacy and safety of evolocumab in paediatric patients (ages 10-17 years) with FH. During the OLE, all patients received monthly 420 mg subcutaneous evolocumab injections. Tests of psychomotor function, attention, visual learning, and executive function were administered at baseline and Weeks 24 and 80 of the OLE. Changes over time were analysed descriptively and using analysis of covariance. Cohen's d statistic was used to evaluate the magnitude of treatment effects. Analysis of covariance results indicated no decrease in performance across visits during 80 weeks of evolocumab treatment for Groton Maze Learning, One Card Learning accuracy, Identification speed, or Detection speed (all P > 0.05). Performance on all tasks was similar for those who received placebo or evolocumab in the RCT (all P > 0.05). For all tests, the least square mean differences between patients who received placebo vs. evolocumab in the parent study were trivial (all Cohen's d magnitude < 0.2). In paediatric patients with FH, 80 weeks of open-label evolocumab treatment had no negative impact on cognitive function. ClinicalTrials.gov identifier: NCT02624869.

55-OR: HSK7653, a Novel Ultralong-Acting DPP-4 Inhibitor, as Monotherapy in Patients With Type 2 Diabetes—A Randomized, Double-Blind, Placebo-Controlled Phase III Trial

Background: HSK7653 is a novel ultralong-acting DPP-4 inhibitor that maintains the average plasma DPP-4 inhibition over 80% for 14 days after 10mg or 25mg dosing. This randomized, double-blind, placebo-controlled phase III trial was conducted to evaluate the efficacy and safety of HSK7653 biweekly as monotherapy for 52 weeks in drug naive type 2 diabetes patients with inadequate glycemic control on diet and exercise. Methods: A total of 475 patients with a mean HbA1c level of 8.1% were randomized to HSK7653 10mg, 25mg or placebo biweekly at a ratio of 1:1:1 for 24 weeks of double-blind treatment, followed by 28 weeks of open-label extension treatment with HSK7653 25mg for all patients. The primary endpoint was the change in HbA1c from baseline at 24 weeks. Results: At week 24, the least-squares mean change in HbA1c from baseline was -0.96% in HSK7653 10mg, -0.92% in HSK7653 25mg and -0.33% in placebo. HSK7653 10mg and 25mg treatment resulted in significant placebo-subtracted changes in HbA1c of -0.63% (95% CI: -0.81%, -0.46%, p&amp;lt;0.0001) and -0.59% (95% CI: -0.77%, -0.42%, p&amp;lt;0.0001), respectively. The percentage of patients achieving HbA1c&amp;lt;7.0% was 44.2% in HSK7653 10mg group and 44.4% in HSK7653 25mg group versus 20.6% in placebo group (p&amp;lt;0.0001 for HSK7653 groups vs. placebo). No meaningful body weight changes were observed in all treatment groups. In the open-label extension treatment (from week 24 to week 52), the sustaining reduction of HbA1c from baseline were observed in HSK7653 10mg switched to 25mg group and HSK7653 25mg maintenance group. There were no excess hypoglycemia events in HSK7653 vs. placebo, and the incidence of adverse events was similar in all groups during the treatment. Conclusions: In people with type 2 diabetes who had inadequate glycemic control on diet and exercise, HSK7653 monotherapy significantly improved glycemic control with well tolerability and safety. Clinical trial information: NCT04556851. Disclosure L.Ji: Other Relationship; Eli Lilly and Company, Novo Nordisk, Merck &amp; Co., Inc., Bayer Inc., Sanofi-Aventis U.S., Roche Pharmaceuticals, MSD Life Science Foundation, AstraZeneca, Boehringer Ingelheim Inc., Abbott, Metronics. F.Bian: None. T.Pan: None. H.Jiang: None. C.Jiang: None. Q.Ren: None.

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.

P253 Ultrasound demonstrates continued improvement in psoriatic arthritis synovitis and enthesitis with secukinumab: 52-week results from a Phase 3 study

Abstract Background/Aims Power Doppler ultrasound (PDUS) is a sensitive non-invasive imaging tool to visualize a wide range of articular and periarticular inflammation in psoriatic arthritis (PsA). ULTIMATE (NCT02662985) is the first large RCT that used ultrasound with Global OMERACT ultrasound synovitis score (GLOESS) as the primary endpoint, to demonstrate early benefits of secukinumab on synovitis in patients with PsA through 12 weeks. Here we report the responsiveness of ultrasound on synovitis and enthesitis, clinical efficacy, and safety of secukinumab up to 52 weeks. Methods This was a 52-week study with 12-week double-blind placebo-controlled treatment followed by 12-week open-label treatment and 6-month open-label extension treatment in all patients. Synovitis and ultrasound enthesitis response were measured by GLOESS and Global OMERACT enthesitis score (definitions 1 and 2) at patient level, respectively. Other assessments across key PsA manifestations of joints (ACR responses), enthesitis, (SPARCC), skin (PASI responses), dactylitis (LDI) and physical function (HAQ-DI) were also evaluated. Data are presented as observed. Results A total of 166 patients were enrolled, of which 90% (75/83) of secukinumab and 83% (69/83) of placebo-secukinumab participants completed 52 weeks. A continued improvement in GLOESS was observed in both secukinumab and placebo-secukinumab groups after switching to active therapy at Week 12 through Week 52 and a similar trend of improvement in Global OMERACT enthesitis score (definition 1 and 2) was observed up to 52 weeks in both groups (Table). At 52 weeks, sustained clinical response rates were observed in secukinumab (ACR20, 89%; ACR50, 68%; ACR70, 48%; PASI 90, 59%; PASI 100, 55%) and placebo-secukinumab groups (ACR20, 84%; ACR50, 72%; ACR70, 47%; PASI 90, 74%; PASI 100, 48%). Mean changes from baseline at Week 52 in HAQ-DI and SPARCC were -3.0 and -0.8 and -3.6 and -0.7 for secukinumab and placebo-secukinumab, respectively. There were no new or unexpected safety findings. Conclusion ULTIMATE demonstrated the responsiveness of ultrasound on both synovitis and enthesitis outcomes in PsA supporting its use in clinical trials, and confirmed the rapid and continued benefits of secukinumab through 52 weeks. Sustained efficacy was also observed across key clinical PsA manifestations with a safety profile consistent with previous reports. Disclosure P.G. Conaghan: Consultancies; AbbVie, AstraZeneca, BMS, Eli Lilly, Galapagos, Gilead, Novartis, Pfizer. Member of speakers’ bureau; AbbVie, AstraZeneca, BMS, Eli Lilly, Galapagos, Gilead, Novartis, Pfizer. M.A. D’Agostino: Consultancies; Sanofi, Novartis, BMS, Janssen, Celgene, Roche, AbbVie, UCB, Eli Lilly. Member of speakers’ bureau; Sanofi, Novartis, BMS, Janssen, Celgene, Roche, AbbVie, UCB, Eli Lilly. G. Schett: Member of speakers’ bureau; AbbVie, BMS, Celgene, Janssen, Eli Lilly, Novartis, Roche, UCB. C. Guerrero: None. P. Hanova: None. T. Cazenave: None. M.S. Stoenoiu: Honoraria; Roche, AbbVie, BMS, Gilead, Jonsson, MSD, Novartis, Pfizer, UCB. Member of speakers’ bureau; Roche, AbbVie, UCB. Grants/research support; Roche, AbbVie, UCB. M. Backhaus: Honoraria; Roche, AbbVie, BMS, Gilead, Jonsson, MSD, Novartis, Pfizer, UCB. Member of speakers’ bureau; Roche, AbbVie, UCB. Grants/research support; Roche, AbbVie, UCB. G. Mouterde: Consultancies; AbbVie, Lilly. Honoraria; AbbVie, BMS, Lilly, Novartis, Pfizer, Roche, Chugai, UCB. Grants/research support; Celgene, Pfizer. M. Boers: Consultancies; BMS, Novartis, Pfizer, GSK. A. Duggan: Other; Employee of Novartis. P. Goyanka: Other; Employee of Novartis MSD. C. Gaillez: Shareholder/stock ownership; Novartis, BMS. Other; Employee of Novartis.

DOP44 Long-term use of ozanimod in patients with moderately to severely active Ulcerative Colitis

Abstract Background Ozanimod was approved by the FDA to treat patients (pts) with moderately to severely active Ulcerative Colitis (UC) based on the results from the 52-week (wk) phase 3 True North (TN) study. We sought to evaluate long-term efficacy and safety of ozanimod. Methods We examined data from an interim analysis of pts in the TN parent study who entered the ongoing TN open-label extension (OLE). Pts entered the TN OLE from the phase 3 TN study if they were non-responders at the end of induction, lost response during maintenance, or completed maintenance treatment, or from the phase 2 Touchstone OLE if they remained at study closure and received once-daily oral ozanimod 0.92 mg (equivalent to ozanimod HCl 1 mg). Clinical remission, clinical response, endoscopic improvement, and corticosteroid (CS)-free remission were evaluated at Wks 46, 94, and 142 in the TN OLE for all pts who entered the OLE from the TN parent study, and in the subset of pts in clinical response at the OLE entry. The data were analysed in the intent-to-treat population using observed cases (OC), which used the number of pts remaining in the study at the corresponding time point, and non-responder imputation (NRI), which used the number of pts remaining in the study at the corresponding time point and those who withdrew before the time point but would have reached the time point if they had stayed. Treatment-emergent adverse events were evaluated from the pooled phase 2 and phase 3 UC studies. Results A total of 823 pts from TN entered the TN OLE; as of the cut-off date (Sept 30, 2020), 64% completed Wk 46, 34% completed Wk 94, and 14% completed Wk 142 of the OLE. The most common reason for discontinuation was lack of efficacy (21%). Baseline demographics were similar as in the TN study. A total of 261 pts were in clinical response at the time of OLE entry. OC analyses showed that the percentage of pts achieving clinical remission, clinical response, endoscopic improvement, and CS-free remission was maintained over time (Table). Efficacy in the responders was higher compared to the total population and was comparable within the endpoints at Wks 46 and 94. Using the more conservative NRI analysis, the proportion of pts achieving each endpoint was lower than in the OC; however, after 94 wks of OLE treatment, 34% of all pts and 55% of the responders still maintained clinical response. No new safety signals were seen with longer-term ozanimod use in the 1158 pts in the pooled population. Conclusion UC pts from the phase 3 TN study demonstrated maintenance of response with long-term ozanimod treatment. These data reflect approximately 2 years of additional ozanimod treatment, with no new safety signals identified.

CT-121: Phase 3 Study of the Efficacy and Safety of Iptacopan (LNP023), an Oral Factor B Inhibitor, in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH) Naïve to Complement Inhibitor Therapy

Context Standard of care in PNH is based on complement C5 inhibition with anti-C5 monoclonal antibodies (MAbs), which are generally effective at treating intravascular hemolysis (IVH), but unmet needs remain. Hematological responses to anti-C5 antibody treatment can be heterogeneous, and a substantial number of patients experience residual anemia associated with breakthrough hemolysis (BTH). Iptacopan, a first-in-class, oral, small-molecule, selective, and reversible complement factor B inhibitor, inhibits both IVH and extravascular hemolysis. In an ongoing Ph2 study (NCT03439839), iptacopan has demonstrated improvements in hematological response and biomarkers of disease activity in PNH adult patients who had active hemolysis, despite eculizumab treatment. Objective APPOINT-PNH study (NCT04820530) will assess iptacopan efficacy and safety in PNH adult patients naive to complement inhibitors, including anti-C5 MAbs. Design The study comprises ≤8-wk screening; 24-wk, single-arm, open-label core treatment; and 24-wk, open-label treatment extension. On completion of week 24, patients who benefit from iptacopan treatment can enter extension. Eligible adult patients (N≈40) have confirmed PNH diagnosis (RBCs and WBCs [granulocyte/monocyte] clone size ≥10%); anemia (mean Hb 1.5× ULN). Key exclusion criteria: prior treatment with complement inhibitor; known or suspected hereditary complement deficiency; history of HSCT; laboratory evidence of bone marrow failure; active, systemic infection ≤14 days preceding study treatment; and history of recurrent, invasive infections caused by encapsulated microorganisms. Primary objective will assess hematologic response, defined as achieving sustained increase in Hb ≥2g/dL (in absence of RBC transfusions). Primary endpoint will evaluate proportion of patients achieving an increase from baseline in Hb ≥2g/dL between D126–D168 (in absence of RBC transfusions between D14–D168). Secondary endpoints include proportion of patients reaching Hb ≥12g/dL; absence of RBC transfusions; changes from baseline in Hb; changes in FACIT-Fatigue scores; changes from baseline in reticulocytes; % change from baseline in LDH; occurrence of BTH; and occurrence of major adverse vascular events (including thrombosis). Additional analyses include safety assessments; evolution of PNH clone size and C3d deposition on RBCs; and other PROs. Conclusions Ph3 studies to assess iptacopan efficacy in a wider population of PNH patients, including those naive to anti-C5 MAbs treatment, are needed. Study sponsored by Novartis Pharmaceuticals Corporation.

Long-term safety and efficacy of bempedoic acid in patients at high risk of atherosclerotic cardiovascular disease: results from the CLEAR Harmony open-label extension study

Abstract Background Bempedoic acid (BA) is an oral first-in-class, ATP-citrate lyase inhibitor that lowers low-density lipoprotein cholesterol (LDL-C) levels in adults with hypercholesterolemia. In the phase 3 CLEAR Harmony study (NCT02666664, n=2230), BA 180 mg for 52 weeks significantly lowered LDL-C at week 12 compared with placebo and was maintained for 52 weeks in hypercholesterolemic patients with atherosclerotic cardiovascular disease (ASCVD) and/or heterozygous familial hypercholesterolemia (HeFH) on stable, maximally tolerated statins. Purpose To report long-term safety, tolerability, and efficacy of BA from the CLEAR Harmony open-label extension (OLE) study (NCT03067441). Methods After completing the 52-week placebo-controlled CLEAR Harmony study, patients immediately entered the OLE and received BA for 78 weeks, followed by a 4-week washout period; the potential cumulative exposure to BA was 2.5 years. The primary endpoint was long-term safety of BA in the OLE. Results A total of 1462 patients enrolled in the OLE (BA n=970; placebo n=492 from CLEAR Harmony). At OLE baseline, mean (SD) age was 66.9 (8.7) years, 73.9% were male, 96.3% had ASCVD, 3.7% had HeFH with or without ASCVD, and all were receiving statins (93.5% moderate or high intensity). At baseline of CLEAR Harmony, patients had mean (SD) LDL-C of 102.9 (29.9) mg/dL (BA) and 99.0 (24.2) mg/dL (placebo). The majority of OLE patients (86.2%, n=1260) completed 78 weeks of BA treatment. At week 12 and 78 of OLE treatment, respectively, mean LDL-C lowering from CLEAR Harmony baseline was –14.9% and –14.4%. A total of 1143 patients (78.2%) reported a treatment-emergent adverse event (TEAE), and 299 (20.5%) reported a serious TEAE. TEAEs of special interest, determined by the therapeutic area or prior observations in preclinical or early clinical studies, occurred at similar rates as CLEAR Harmony (creatine kinase elevations, 1.8%; gout, 2.6%; hepatic enzyme elevations, 2.0%; hypoglycemia, 1.2%; muscular disorders, 8.5%; neurocognitive disorders, 0.9%; new onset/worsening diabetes mellitus, 5.5%; renal disorders, 2.8%) with biochemical changes that were stable over the course of the study and approached baseline levels after treatment discontinuation. Overall, 114 patients (7.8%) reported a TEAE leading to discontinuation of BA (most common: myalgia [0.6%], muscle spasm [0.5%]). Conclusion Durable lipid lowering was observed through 78 weeks of BA treatment and patient adherence to BA therapy was high (86.2%). Overall safety during the OLE was similar to results reported in the 52-week-long CLEAR Harmony study and the overall BA phase 3 clinical program, with no new safety findings. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Esperion Therapeutics, Inc., funded the research for this study and provided writing support for this abstract. Medical writing assistance was provided by Agnella Izzo Matic, PhD, CMPP, and Kelly M Cameron, PhD, CMPP, of JB Ashtin.

Inhaled Molgramostim Therapy in Autoimmune Pulmonary Alveolar Proteinosis

BackgroundAutoimmune pulmonary alveolar proteinosis (aPAP) is a rare disease characterized by progressive surfactant accumulation and hypoxemia. It is caused by disruption of granulocyte–macrophage colony-stimulating factor (GM-CSF) signaling, which pulmonary alveolar macrophages require to clear surfactant. Recently, inhaled GM-CSF was shown to improve the partial pressure of arterial oxygen in patients with aPAP.MethodsIn a double-blind, placebo-controlled, three-group trial, we randomly assigned patients with aPAP to receive the recombinant GM-CSF molgramostim (300 μg once daily by inhalation), either continuously or intermittently (every other week), or matching placebo. The 24-week intervention period was followed by an open-label treatment-extension period. The primary end point was the change from baseline in the alveolar–arterial difference in oxygen concentration (A-aDo2) at week 24.ResultsIn total, 138 patients underwent randomization; 46 were assigned to receive continuous molgramostim, 45 to receive intermittent molgramostim, and 47 to receive placebo. Invalid A-aDo2 data for 4 patients (1 in each molgramostim group and 2 in the placebo group) who received nasal oxygen therapy during arterial blood gas measurement were replaced by means of imputation. For the primary end point — the change from baseline in the A-aDo2 at week 24 — improvement was greater among patients receiving continuous molgramostim than among those receiving placebo (−12.8 mm Hg vs. −6.6 mm Hg; estimated treatment difference, −6.2 mm Hg; P=0.03 by comparison of least-squares means). Patients receiving continuous molgramostim also had greater improvement than those receiving placebo for secondary end points, including the change from baseline in the St. George’s Respiratory Questionnaire total score at week 24 (−12.4 points vs. −5.1 points; estimated treatment difference, −7.4 points; P=0.01 by comparison of least-squares means). For multiple end points, improvement was greater with continuous molgramostim than with intermittent molgramostim. The percentages of patients with adverse events and serious adverse events were similar in the three groups, except for the percentage of patients with chest pain, which was higher in the continuous-molgramostim group.ConclusionsIn patients with aPAP, daily administration of inhaled molgramostim resulted in greater improvements in pulmonary gas transfer and functional health status than placebo, with similar rates of adverse events. (Funded by Savara Pharmaceuticals; IMPALA ClinicalTrials.gov number, NCT02702180.)

M208. MEASURES OF COGNITION AND SOCIAL FUNCTIONING IN SCHIZOPHRENIA PATIENTS RECEIVING SEP-363856

BackgroundSEP-363856 is a novel trace amine associated receptor-1 (TAAR1)/5-HT1A agonist with no dopamine-D2/5-HT2A antagonist activity. SEP-363856 showed significant antipsychotic efficacy in patients with schizophrenia, and a safety and tolerability profile similar to placebo and consistent with a non-D2 mechanism of action. Here, we examined measures of cognition and social functioning in schizophrenia patients receiving SEP-363856.MethodsPatients aged 18–40 years with an acute exacerbation of schizophrenia were randomized, double-blind (DB), to 4-weeks of flexible-dose treatment with once daily SEP-363856 (N=120; 50 or 75 mg) or placebo (N=125). Patients (N=156) entering a subsequent 26-week open-label (OL) extension study were evaluated utilizing the Cogstate Brief Battery, administered at DB baseline and week 4, and OL baseline and weeks 12 and 26. Standardized z-scores were calculated for the Cogstate composite and subscale tasks (Detection task, Identification task, One Card Learning task, One Back task). The University of California San Diego Performance Based Skills Assessment (UPSA-B) scale was assessed at the same time-points, as were the following psychiatric scales: Positive and Negative Syndrome Scale (PANSS), the Brief Negative Symptom Scale (BNSS), the Montgomery–Åsberg Depression Rating Scale (MADRS), the Clinical Global Impression Scale, severity scale (CGI-S), and the Pittsburgh Sleep Quality Index global score (PSQI-global). Pearson correlation analyses were performed between DB baseline to Week 26 change in Cogstate composite and subscale scores and Week 26 change in the psychiatric scale scores.ResultsSmall improvements, from DB baseline to Week 26, were observed in standardized scores on the Cogstate composite (+0.29), Identification task (+0.19), Detection task (+0.28); One Card learning task (+0.33); and One Back task (+0.33). Improvement from OL baseline at Week 26 was also observed on the mean [SD] UPSA-B total score (+6.2 [11.6]). At DB baseline, there were no correlations between CogState composite score and individual test scores with any of the psychiatric scales. Week 26 improvement in the following Cogstate composite and subscale tasks were correlated with Week 26 improvement in the following psychiatric scale scores: Cogstate composite score (PANSS total, r=-0.26; BNSS total, r=-0.31; CGI-S, r=-0.30; MADRS total, r=-0.23; PSQI-global, r=-0.23); Identification task (PANSS total, r=-0.30; BNSS total, r=-0.30), Detection task (BNSS total, r=-0.30; CGI-S, r=-0.28; PSQI-global, r=-0.23); One Card learning task (MADRS total, r=-0.29); and One Back task (PANSS total, r=-0.26).DiscussionDuring 6-months of open-label extension treatment with SEP-363856, improvement in overall functioning was observed on the UPSA-B scale; and small but consistent improvement in cognition was noted in the Cogstate composite and subscale task scores. Endpoint reduction in the severity of schizophrenia-related symptomatology (eg, on the PANSS, BNSS, MADRS, insomnia) were associated with modest correlations, in the range of 0.2 to 0.3, in cognitive performance as measured by the Cogstate composite and subscale task scores.

Long-term use of adalimumab as monotherapy after attainment of low disease activity with adalimumab plus methotrexate in patients with rheumatoid arthritis

ObjectiveTo evaluate long-term clinical, functional and radiographic outcomes in an open-label extension (OLE) study in patients with rheumatoid arthritis (RA) receiving adalimumab monotherapy or adalimumab+methotrexate following attainment of low disease...

Open-label therapy with alirocumab in patients with heterozygous familial hypercholesterolemia: Results from three years of treatment

BackgroundPCSK9 inhibition with alirocumab significantly reduced LDL-C levels in trials of up to 78weeks' duration in patients with heterozygous familial hypercholesterolemia (HeFH). We report results from 3years of an ongoing open-label treatment extension (NCT01576484) to a 12-week double-blind trial in HeFH patients (NCT01266876). MethodsPatients who completed the parent study and were receiving stable daily statin±ezetimibe could enter the open-label extension, where they received alirocumab 150mg every 2 weeks (Q2W) subcutaneously (n=58). The primary endpoint was safety (treatment-emergent adverse events, TEAEs). Efficacy endpoints included the percentage change in LDL-C from baseline at Week 24. Safety and efficacy data were available up to Weeks 156 and 148, respectively. ResultsMean baseline LDL-C was 150.7mg/dL (3.9mmol/L), despite all patients being on a statin (76% on high-intensity statin; 72% also receiving ezetimibe). Over 156weeks, 54 (93.1%) patients experienced a TEAE, 12 (20.7%) experienced a serious TEAE, and two (3.4%) discontinued due to a TEAE. Injection site reactions occurred in 21 (36.2%) patients. Mean (SD) reduction in LDL-C from baseline to Week 24 was 65.4 (21.1)%, with reductions maintained through 148weeks (Week 148 reduction: 56.0 [23.8]%). Mean apolipoprotein B reduction was 50.9% and median lipoprotein (a) reduction was 22.5% at Week 24 (46.1% and 25.6% at Week 148, respectively). ConclusionsOpen-label treatment for 3years with alirocumab 150mg Q2W, administered with background statin±ezetimibe, was generally well-tolerated and had a safety profile comparable with that seen in the overall alirocumab clinical trial program. Alirocumab provided significant, sustained LDL-C reductions.

WS14.1 Ivacaftor improves exercise capacity in patients with G551D CF gene mutations

Introduction G551D is a CFTR mutation that results in impaired chloride channel function in Cystic Fibrosis (CF). Ivacaftor, a CFTR potentiating agent improves lung function and sweat chloride but its effect on exercise is unproven. Objectives To evaluate exercise capacity in response to correction of the chloride channelopathy with ivacaftor. Methods In a placebo-controlled crossover study of ivacaftor over 4 months with a 3 month open label extension we performed cardiopulmonary exercise tests (CPET) at six time points. 20 patients were included in the study. The primary outcome was VO2max as a percentage of baseline at the end of the crossover study (END X) and 3 month open label extension (OLE). A training program was not included in the study. Results There was a stepwise increase in maximal exercise capacity based on VO2max in the treated group above baseline at END X and 3 month OLE treatment periods. FEV1 and sweat chloride were also improved as expected. EndpointEnd X, mean (95% CI)OLE, mean (95% CI)%Δ absolute exercise time8.0 (1.4–14.6) * 12.1 (5.8–18.4) *** %Δ VO2max, ml/kg/min6.7 (2.7–10.8) ** 12.6 (6.3–18.9) *** %Δ VO2 ml/min7.8 (3.7–12.0) *** 15.6 (9.7–21.4) *** %Δ Watts5.0 (1.4–8.6) ** 10.9 (5.6–16.3) *** *p Conclusion Treatment of G551D patients with ivacaftor has a positive effect on exercise capacity which is independent of training. Improved VO2max has not been previously examined in clinical trials with ivacaftor and may have prognostic implications for patients with the G551D mutation. Supported by a grant from Vertex Inc.

Efficacy and Safety of Celecoxib in Chinese Patients with Ankylosing Spondylitis: A 6-Week Randomized, Double-Blinded Study with 6-Week Open-Label Extension Treatment

BackgroundNonsteroidal anti-inflammatory drugs are the first-line option for treating ankylosing spondylitis (AS) in China. However, no large-scale controlled trials have been conducted in this ethnic population. ObjectiveTo evaluate the efficacy and safety of 6 weeks’ treatment with celecoxib in patients with AS in China. MethodsThis Phase 3, double-blind, parallel-group study randomized patients with AS aged ≥18 to 65 years 1:1 to receive celecoxib 200 mg once daily or diclofenac sustained release 75 mg once daily. After 6 weeks, patients could use celecoxib 400 mg once daily or maintain blinded therapy. The primary efficacy end point was mean change from baseline at Week 6 for Patient’s Global Assessment of Pain Intensity score (100-mm visual analog scale). Noninferiority was established if the upper bound of the CI was <10 mm. Secondary objectives included patients’ and physicians’ assessments of disease activity, change from baseline in C-reactive protein level, and safety. ResultsIn the per-protocol analysis set the least squares mean change from baseline in the Patient’s Global Assessment of Pain Intensity score at Week 6 was –23.8 mm and –27.1 mm in patients receiving celecoxib (n = 111) and diclofenac (n = 108), respectively. The 2-sided 95% CI for the treatment difference (celecoxib – diclofenac) was –2.2 to 8.8. Overall, 4.2% and 6.7% of patients in the celecoxib and diclofenac groups, respectively, reported treatment-related adverse events. All were mild to moderate in severity. ConclusionsCelecoxib 200 mg once daily is noninferior to diclofenac sustained release 75 mg once daily for pain treatment in Chinese patients with AS. ClinicalTrials.gov identifier: NCT00762463.

FRI0249 Long-term safety and efficacy of treatment with subcutaneous abatacept in japanese patients with ra who were mtx inadequate responders – 76-week results

BackgroundSubcutaneous (SC) abatacept demonstrated comparable safety and efficacy to intravenous (IV) abatacept after 24 weeks in Japanese patients with active RA.1ObjectivesTo assess the long-term safety, immunogenicity and efficacy of SC...

Tophus burden reduction with pegloticase: results from phase 3 randomized trials and open-label extension in patients with chronic gout refractory to conventional therapy

IntroductionTwo replicate randomized, placebo-controlled six-month trials (RCTs) and an open-label treatment extension (OLE) comprised the pegloticase development program in patients with gout refractory to conventional therapy. In the RCTs, approximately 40% of patients treated with the approved dose saw complete response (CR) of at least one tophus. Here we describe the temporal course of tophus resolution, total tophus burden in patients with multiple tophi, tophus size at baseline, and the relationship between tophus response and urate-lowering efficacy.MethodsBaseline subcutaneous tophi were analyzed quantitatively using computer-assisted digital images in patients receiving pegloticase (8 mg biweekly or monthly) or placebo in the RCTs, and pegloticase in the OLE. Tophus response, a secondary endpoint in the trials, was evaluated two ways. Overall tophus CR was the proportion of patients achieving a best response of CR (without any new/enlarging tophi) and target tophus complete response (TT-CR) was the proportion of all tophi with CR.ResultsAmong 212 patients randomized in the RCTs, 155 (73%) had ≥1 tophus and 547 visible tophi were recorded at baseline. Overall tophus CR was recorded in 45% of patients in the biweekly group (P = 0.002 versus placebo), 26% in the monthly group, and 8% in the placebo group after six months of RCT therapy. TT-CR rates at six months were 28%, 19%, and 2% of tophi, respectively. Patients meeting the primary endpoint of sustained urate-lowering response to therapy (responders) were more likely than nonresponders to have an overall tophus CR at six months (54% vs 20%, respectively and 8% with placebo).Both overall tophus CR and TT-CRs increased with treatment duration in the OLE, reaching 70% (39/56) of patients and 55% (132/238) of target tophi after one year of treatment in patients receiving pegloticase during both the RCTs and OLE. At that time point, more tophi had resolved in responders (102/145 or 70% of tophi) than nonresponders (30/93; 32%).ConclusionsPegloticase reduced tophus burden in patients with refractory tophaceous gout, especially those achieving sustained urate-lowering. Complete resolution of tophi occurred in some patients by 13 weeks and in others with longer-term therapy.Trial registrationsNCT00325195, NCT01356498

Perampanel Study 207: long-term open-label evaluation in patients with epilepsy

Evaluate interim long-term tolerability, safety and efficacy of adjunctive perampanel, a novel α-amino-3-hydroxy-5-methyl-5-isoxazolepropionic acid (AMPA)-receptor antagonist, in patients with refractory partial-onset seizures. Study 207, an open-label extension (OLE) study (ClinicalTrials.gov identifier: NCT00368472), enrolled patients (18-70years) who completed one of two randomized, placebo-controlled, dose-escalation Phase II studies. The OLE Treatment Phase comprised a 12-week Titration Period (2mg increments of perampanel every 2weeks to 12mg/day, maximum) and a Maintenance Period, during which patients continued treatment up to a planned maximum of 424weeks (~8years). Interim analysis data cut-off date was 1 December, 2010. Of 180 patients completing the Phase II studies, 138 enrolled in study 207. At the time of interim analyses (approximately 4years after study start), over a third (n=53, 38.4%) remained on perampanel; 41.3% (n=57) of patients had >3years of exposure; and 13.0% (n=18) had at least 4years' exposure. Mean±standard deviation (SD) duration of exposure was 116±75weeks and mean±SD dose during the OLE Maintenance Period was 7.3±3.3mg. No new safety signals emerged with long-term treatment. Consistent with previous studies, the most common treatment-emergent adverse events were as follows: dizziness, headache and somnolence. Overall median (range) per cent change from baseline in seizure frequency per 28days during open-label treatment was -31.5% (-99.2 to 512.2). Long-term - up to 4years - adjunctive perampanel had a favourable tolerability profile in patients with refractory partial-onset seizures. Improvements in seizure control were maintained with long-term treatment.

Open-Label Treatment With Olanzapine for Patients With Borderline Personality Disorder

This report presents efficacy and safety outcomes for patients with borderline personality disorder (BPD) treated with olanzapine for up to 24 weeks. In 2 concurrent studies, patients received open-label olanzapine for 12 weeks after 12 weeks of double-blind olanzapine or placebo. Open-label dosing started at 2.5 or 5 mg/d and could be increased up to 20 mg/d (study 1) or 15 mg/d (study 2). The primary efficacy measure was open-label baseline-to-endpoint change in Zanarini Rating Scale for BPD (ZAN-BPD) total score. Of 472 patients who completed the double-blind acute phase, 444 entered and 320 (72.1%) completed 12 weeks of open-label extension treatment. Mean ZAN-BPD total scores at the start of the acute phase were approximately 17, indicating moderate symptom severity. Mean ZAN-BPD total scores ranged from 7.8 to 10.5 at the start of the open-label treatment and decreased to 5.7 to 6.5, indicating mild symptom severity, by the end of the open-label treatment. Patients taking placebo during the acute phase showed increases in weight, prolactin level, and other laboratory values during open-label olanzapine treatment similar in magnitude to increases seen in olanzapine-treated patients during the acute phase. Patients proceeding from olanzapine during the acute phase to open-label olanzapine showed smaller changes in weight and laboratory values. In conclusion, these results suggest that continued therapy with olanzapine may sustain and build upon improvements seen with acute olanzapine treatment of patients with BPD. However, no medication is currently approved for treatment of BPD, and physicians should carefully weigh potential benefits and risks of antipsychotic treatment in this population.

AOSOP6 Results from the 2-year open-label extension treatment phase of a pivotal phase 3 study of denosumab in patients with breast cancer and bone metastases previously treated with zoledronic acid or denosumab

Background Denosumab was superior to zoledronic acid (ZA) in reducing the risk of a first on-study skeletal-related event (SRE; HR, 0.82; 95% confidence interval (CI) 0.71, 0.95; p = 0.01) in patients with breast cancer and bone metastases (BMs; Stopeck et al., 2010). All patients who remained on treatment after the primary analysis were offered open-label (OL) denosumab for a pre-specified 2-year extension phase. Methods Women with BMs secondary to breast cancer ( N = 2046) were randomly assigned to subcutaneous denosumab 120 mg or IV ZA 4 mg (adjusted for renal function) Q4W. Patients who completed this double-blind, double-dummy treatment phase were offered OL denosumab Q4W. Patients who did not participate in the OL phase were followed up for survival every 12 weeks for up to 2 years after their last dose of investigational drug. Findings Of the 752 patients who completed the double-blind phase, 667 (89%) chose to receive OL denosumab: 325 initially randomly assigned to denosumab (DD) and 342 to ZA (ZD). Total median (Q1, Q3) cumulative denosumab exposure in DD patients was 19.3 months (9.2, 32.2) (range 0.9–59.8 months). Adverse events (AEs) were comparable between groups ( n = 283/318 [89%] for DD; n = 303/334 [91%] ZD) during the OL phase; 20 and 18 patients, respectively, reported osteonecrosis of the jaw; cumulative incidence was 4.7% in DD patients and 3.5% in ZD patients for the entire study duration of 5 years. Hypocalcaemia was comparable between groups ( n = 12 DD; n = 9 ZD). Serious AEs were reported in 126 (39.6%) DD patients and 133 (39.8%) ZD patients. Overall survival was similar between the groups for the entire study: median 34.4 months (95% CI 31.5, 39.3) and 34.2 months (95% CI 31.0, 37.6), respectively. Interpretation This OL extension treatment phase confirmed the safety profile of denosumab in patients with breast cancer with BMs receiving up to 5 years of monthly denosumab therapy or switching to denosumab after up to 3 years of ZA. Funding Funding was provided by Amgen Inc. A.T. Stopeck is a consultant for Amgen and Novartis; A. Lipton is a member of the speakers’ bureau, is a consultant, has received research support from Amgen and Novartis, and has provided expert testimony for Novartis; M. Martin is a consultant for Amgen; J-J. Body is a consultant for and has received lecture fees from both Amgen and Novartis; A. Paterson has received honoraria for speaking from Amgen, Roche, and Novartis; G.G. Steger has received travel grants and attended advisory boards for Amgen and Novartis; K. Tonkin has no disclosures; R.H. de Boer has no disclosures; Y. Fujiwara, Chugai Pharmaceutical Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Novartis Pharma KK, Janssen Pharmaceutical KK, and Takeda Bio Development Center Limited; D. Yardley has no disclosures; J. Jassem has no disclosures; T. Takano is a medical consultant for Daiichi Sankyo; P. Solal-Celigny has no disclosures; and M. Fan and A. Braun are employed by Amgen and own stock.

Long‐term outcomes of interruption and retreatment vs. continuous therapy with adalimumab for psoriasis: subanalysis of REVEAL and the open‐label extension study

REVEAL was a 52-week study of adalimumab for moderate to severe psoriasis. At Week 33, adalimumab-treated patients with sustained responses (PASI ≥75 at Weeks 16 and 33) were re-randomized to receive adalimumab or placebo. Subsequently, they could receive adalimumab in an open-label extension (OLE) study. To compare long-term efficacy and safety of adalimumab 40 mg every other week (eow), given as continuous treatment or with one period of interruption followed by retreatment. Patients who were re-randomized to adalimumab or placebo at REVEAL Week 33 and received ≥ 1 dose of OLE adalimumab were analysed as the continuous and retreatment groups, respectively, for >2 years of OLE treatment with adalimumab 40 mg eow. LOCF was used for missing efficacy data. At OLE Weeks 0, 12 and 24, PASI 75 response rates were 84%, 84%, 86% with continuous treatment (N = 233) vs. 45%, 71%, 79% with retreatment (N = 227). Thereafter, efficacies were slightly greater for continuous treatment but similar between groups, with PASI 75 response rates at OLE Week 108 of 75% vs. 73% respectively. Retreatment was most effective for patients with ≥ PASI 50 responses when retreatment was initiated. Adverse event rates for retreatment were equal to or lower than those for continuous treatment. In psoriasis patients with sustained PASI 75 responses to adalimumab, long-term efficacy of retreatment after a ≤ 19-week interruption was similar to efficacy achieved with > 3 years continuous treatment. Adalimumab retreatment provided the best results when initiated before responses had declined below PASI 50.