Open-label Extension Period Research Articles

A PHASE 2/3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF MITAPIVAT IN PATIENTS WITH SICKLE CELL DISEASE

The key pathology in sickle cell disease (SCD), a life-threatening, hereditary hemoglobin (Hb) disorder, is red blood cell (RBC) sickling due to polymerization of deoxygenated sickle Hb (HbS), which can be exacerbated by increased levels of the glycolytic metabolite 2,3-diphosphoglycerate (2,3-DPG) and decreased ATP. Sickled RBCs are rigid, non-deformable, and fragile, resulting in vaso-occlusive pain and chronic hemolysis. Current SCD treatment options are limited; therefore, there is an unmet need for safe, effective therapies that alleviate both anemia and pain. Activation of the key RBC glycolytic enzyme pyruvate kinase (PKR) by oral mitapivat decreases 2,3-DPG and increases ATP, which may reduce HbS polymerization, RBC sickling, and hemolysis in SCD. Data from the phase (ph) 1 National Institutes of Health multiple ascending dose study of up to 100 mg mitapivat twice daily (BID) in patients with SCD (NCT04000165) showed that mitapivat was safe and tolerable, increased ATP and decreased 2,3-DPG in a dose-dependent manner, and improved anemia and hemolysis. Here we report the study design of RISE UP (NCT05031780, EudraCT: 2021-001674-34), a ph 2/3, double-blind, randomized, placebo (PBO)-controlled, multicenter study evaluating the efficacy and safety of mitapivat in patients (pts) with SCD. Eligible: pts aged ≥16 yrs (≥18 yrs [France and Germany]) with documented SCD (HbSS, HbSC, HbSβ 0 /HbSβ + thalassemia, other variants), 2–10 sickle cell pain crises (SCPCs; acute pain requiring intervention, acute chest syndrome, priapism, hepatic or splenic sequestration) in the prior 12 months, and Hb 5.5–10.5 g/dL. If on hydroxyurea (HU), the dose must be stable for ≥ 90 days before starting study drug. Ineligible: pts receiving regular blood transfusions, with severe kidney or hepatobiliary disease, current SCD therapies except HU, or prior gene therapy, bone marrow or stem cell transplantation. In the double-blind ph 2 part, 69 pts will be randomized (1:1:1) to 50 mg or 100 mg mitapivat, or PBO BID for 12 weeks (wk). The primary objective is to determine the recommended ph 3 mitapivat dose by evaluating anemia and safety vs PBO via the following endpoints: Hb response (≥ 1.0 g/dL increase in average (avg) Hb concentration over Wk 10–12 vs baseline [BL]), and type, severity, and relationship of adverse events (AEs) and serious AEs. In the double-blind ph 3 part, 198 pts who did not participate in ph 2 will be randomized (2:1) to the selected ph 3 mitapivat dose or PBO BID for 52 wk. The primary objectives are to determine the effect of mitapivat vs PBO on anemia, measured by Hb response (≥ 1.0 g/dL increase in avg Hb concentration over Wk 24–52 vs BL), and the effect of mitapivat vs PBO on SCPC, measured by annualized rate of SCPCs. Key secondary endpoints: avg change from BL in Hb concentration, indirect bilirubin, percent reticulocyte, and Pt-Reported Outcomes Measurement Information System ® Fatigue 13a Short Form score over Wk 24–52; and annualized frequency of SCPC admissions. Pts who complete the double-blind period will be eligible to receive mitapivat in the open-label extension period in each ph. Pending. N/A. This ph 2/3 study will investigate the efficacy and safety of mitapivat in pts with SCD. Enrollment is currently ongoing.

EFFICACY AND SAFETY OF NIPOCALIMAB, AN FCRN BLOCKER, IN WARM AUTOIMMUNE HEMOLYTIC ANEMIA (WAIHA): ENERGY PHASE 2/3 STUDY DESIGN

Warm autoimmune hemolytic anemia (wAIHA) is characterized by the destruction of red blood cells (RBCs) by pathogenic autoantibodies which bind to RBCs and lead to their clearance in the spleen and liver. Patients with wAIHA can experience acute worsening of anemia, which can be a medical emergency, and have an increased risk of thromboembolic events and premature death. Nipocalimab is a fully human, aglycosylated, effectorless IgG1 monoclonal antibody that blocks the IgG binding site on the neonatal Fc receptor (FcRn) with high affinity. FcRn, which is expressed in endothelial cells, is responsible for recycling IgG into the circulation and for the relatively long half-life of IgG antibodies compared to other Igs. It is expected that nipocalimab, by blocking IgG binding to FcRn, will prevent IgG recycling and lower pathogenic IgG autoantibodies that cause many autoantibody diseases, including wAIHA. Nipocalimab has been studied in multiple phase 1 studies in healthy subjects and in a completed phase 2 study in subjects with Generalized Myasthenia Gravis (gMG). Treatment with nipocalimab was associated with rapid and durable total serum IgG and pathogenic IgG autoantibody reduction and meaningful clinical response. Here we share the rationale and study design for an adaptive, phase 2/3 multicenter, randomized, double-blind, placebo-controlled study in patients with wAIHA whose aim is to evaluate the efficacy, safety, tolerability, PK, and PD of nipocalimab compared with placebo (NCT04119050). Male or female subjects ≥18 years of age who have been diagnosed with primary or secondary wAIHA and have not experienced a sufficient response or have not tolerated currently available treatments will be included in the study. Subjects with cold antibody AIHA, cold agglutinin syndrome, mixed type (i.e., warm and cold) AIHA, or paroxysmal cold hemoglobinuria will be excluded. Participants will be randomized 1:1:1 to receive nipocalimab at two different dose schedules or placebo. Following completion of 24 weeks of double-blind treatment, participants may enter an open-label extension period to receive nipocalimab. The primary endpoint is percentage of participants achieving durable response of improvement in hemoglobin (Hgb). The main secondary endpoints are change from baseline in the total score from the FACIT-Fatigue Scale, number of participants who attain normal lactate dehydrogenase, normal haptoglobin, and normal indirect bilirubin levels at a minimum of 3 consecutive visits after baseline. ENERGY is a phase 2/3 study that will evaluate the efficacy and safety of nipocalimab in wAIHA. ENERGY is currently enrolling globally. IM received research support from Alexion, Annexon, Incyte, Kezar, Momenta, Rigel, and Sanofi; and served as a consultant for Apellis, Janssen, Momenta, Novartis, Rigel, and Sanofi. BF is a consultant of Alexion, Amgen, Janssen, Momenta, and Novartis. DC is an employee of Janssen Global Services, LLC, which is a wholly owned subsidiary of Johnson & Johnson, and may own stock or stock options in Johnson & Johnson; was an employee of Momenta. AMBP is an employee of Janssen Latin America, which is a wholly owned subsidiary of Johnson & Johnson, and may own stock or stock options in Johnson & Johnson. MHJ was an employee of Momenta.

Assessment of efficacy and safety of volanesorsen for treatment of metabolic complications in patients with familial partial lipodystrophy: Results of the BROADEN study: Volanesorsen in FPLD; The BROADEN Study

BackgroundVolanesorsen, an antisense oligonucleotide, is designed to inhibit hepatic apolipoprotein C-III synthesis and reduce plasma apolipoprotein C-III and triglyceride concentrations. ObjectiveThe present study assessed efficacy and safety of volanesorsen in patients with familial partial lipodystrophy (FPLD) and concomitant hypertriglyceridemia and diabetes. MethodsBROADEN was a randomized, placebo-controlled, phase 2/3, 52-week study with open-label extension and post-treatment follow-up periods. Patients received weekly subcutaneous volanesorsen 300 mg or placebo. The primary endpoint was percent change from baseline in fasting triglycerides at 3 months. Secondary endpoints included relative percent change in hepatic fat fraction (HFF), visceral adiposity, and glycated hemoglobin levels. ResultsForty patients (11 men, 29 women) were enrolled, majority of whom were aged <65 years (mean, 47 years) and White. Least squares mean (LSM) percent change in triglycerides from baseline to 3 months was −88% (95% CI, −134 to −43) in the volanesorsen group versus –22% (95% CI, −61 to 18) in the placebo group, with a difference in LSM of −67% (95% CI, –104 to –30; P=0.0009). Volanesorsen induced a significant LSM relative reduction in HFF of 53% at month 12 versus placebo (observed mean [SD]: 9.7 [7.65] vs. 18.0 [8.89]; P=0.0039). No statistically significant changes were noted in body volume measurements (fat, liver, spleen, visceral/subcutaneous adipose tissue) or glycated hemoglobin. Serious adverse events in patients assigned to volanesorsen included 1 case each of sarcoidosis, anaphylactic reaction, and systemic inflammatory response syndrome. ConclusionIn BROADEN, volanesorsen significantly reduced serum triglyceride levels and hepatic steatosis in patients with FPLD.

34321 Bimekizumab efficacy and safety through 96 weeks in patients with moderate to severe plaque psoriasis: Results from the open-label extension period of the BE RADIANT phase 3b trial

Introduction: Through 1 year of the BE RADIANT phase 3b trial, superior rates of complete skin clearance were observed with bimekizumab (BKZ) vs secukinumab (SEC). No new safety signals were identified.

33817 Bimekizumab efficacy and safety in patients with moderate to severe plaque psoriasis who switched from secukinumab: Results from the open-label extension period of the BE RADIANT phase 3b trial

Introduction: Switching biologics can improve efficacy without the impairment of safety in the treatment of psoriasis. Methods: In BE RADIANT, patients were randomized 1:1 to bimekizumab (BKZ) 320 mg every 4 weeks (wks)(Q4W) (Q4W or Q8W from Wk16) or secukinumab (SEC). Patients who completed the 48-wk double-blinded period could continue to the open label extension (OLE); all received BKZ 320 mg Q4W or Q8W through Wks48–96. We report efficacy for patients who switched from SEC to BKZ by Wk48 PASI90 response. Missing data were imputed as modified nonresponse. Patients who discontinued treatment due to lack of efficacy were considered nonresponders; multiple imputation was used for other missing data. Safety data are reported through Wks48–68 and Wks68–96. Results: At Wk48, 318 SEC-randomized patients continued to the OLE. 53 (16.7%) of these patients did not achieve PASI90. After switching to BKZ, responses improved (79.2% achieved PASI90 and 50.9% achieved PASI100 at Wk96). At Wk48, 256/318 (80.5%) SEC-randomized patients who entered the OLE achieved PASI90. Among these Wk48 PASI90 responders, 95.2% maintained PASI90 at Wk96. In SEC PASI90 responders, PASI100 response increased from 65.2% at Wk48 to 79.9% at Wk96. No clinically relevant differences in safety outcomes for patients who switched from SEC to BKZ were observed between Wks48–68 and Wks68–96. Conclusions: SEC PASI90 nonresponders demonstrated improvements in complete/near complete skin clearance after switching to BKZ. Among SEC PASI90 responders, PASI90 response was maintained and PASI100 response increased after switching. There were no unexpected safety findings in patients who switched.

Risankizumab for the Treatment of Moderate to Severe Plaque Psoriasis in the Russian Federation.

IntroductionRisankizumab has demonstrated efficacy and safety in phase 3 studies in patients with moderate to severe plaque psoriasis. This randomized clinical trial assessed the efficacy and safety of risankizumab in patients with moderate to severe plaque psoriasis in the Russian Federation.MethodsPatients with moderate to severe plaque psoriasis were randomized 4:1 to 16 weeks of double-blind treatment with risankizumab 150 mg or placebo (period A; dosing at baseline and week 4) followed by an open-label extension (period B) during which all patients received risankizumab 150 mg at weeks 16, 28, and 40 and were followed up to week 52. The primary study endpoint was the proportion of patients achieving ≥ 90% improvement in the Psoriasis Area and Severity Index (PASI 90) at week 16, and secondary endpoints included Static Physician’s Global Assessment scores and the Dermatology Life Quality Index. Treatment-emergent adverse events were monitored throughout the two study periods.ResultsOf the 50 patients who entered period A, 41 were randomized to receive risankizumab and 9 to receive placebo. Forty-eight patients entered period B, and 47 completed the study. A significantly larger proportion of risankizumab-treated patients achieved PASI 90 at week 16 compared with placebo-treated patients [response rate difference: 38.8% (95% CI 7.8–69.7%; P = 0.035)]. Consistently higher proportions of risankizumab-treated patients achieved secondary endpoints compared with the placebo-treated patients. Safety profiles were similar between the treatment groups, and no patients discontinued the study drug owing to adverse events.ConclusionRisankizumab was efficacious and well tolerated in patients with moderate to severe plaque psoriasis in the Russian Federation.Trial RegistrationClinicalTrials.gov NCT03518047.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-022-00776-0.

Long-term safety of satralizumab in neuromyelitis optica spectrum disorder (NMOSD) from SAkuraSky and SAkuraStar

BackgroundThis analysis evaluated long-term safety findings from the SAkuraSky and SAkuraStar studies with satralizumab in patients with neuromyelitis optica spectrum disorder (NMOSD). MethodsSAkuraSky (satralizumab in combination with baseline immunosuppressive therapy; IST) and SAkuraStar (satralizumab monotherapy) are international, multicenter, randomized, placebo-controlled, phase 3 studies consisting of a double-blind (DB) period followed by an open-label extension (OLE). The overall satralizumab treatment (OST) period safety population comprised patients receiving ≥1 dose of satralizumab in the DB and/or OLE periods (cut-off date: 22 February 2021). Safety was evaluated in the DB and OST periods. ResultsIn the SAkuraSky DB period, patients received satralizumab (n = 41) or placebo (n = 42) in addition to stable baseline IST; 75 patients were included in the OST population. In the SAkuraStar DB period, 63 patients received satralizumab monotherapy and 32 received placebo; 91 patients were included in the OST population. Median treatment exposure in the OST period was 4.4 years (range 0.1–7.0) in SAkuraSky and 4.0 years (range 0.1–6.1) in SAkuraStar. Rates of adverse events (AEs per 100 patient-years) and serious AEs in the OST period were comparable with satralizumab and placebo in the DB periods of both studies. Similarly, overall rates of infections and serious infections were consistent between the OST and DB periods with satralizumab, with no increase in rates of infections or serious infections over time. In the OST periods, longer exposure to satralizumab was not associated with a higher risk of severe (grade ≥3) laboratory changes versus the DB periods. No deaths or anaphylactic reactions to treatment with satralizumab were reported during the OST periods of both studies. ConclusionThe safety profile of satralizumab as a monotherapy or in combination with IST was maintained in the OLE, and no new safety concerns versus the DB period were observed. Clinical trial registrationClinicalTrials.gov identifiers: NCT02028884 (SAkuraSky) and NCT02073279 (SAkuraStar).

P830: CROVALIMAB MAINTAINS CLINICAL BENEFIT OVER LONG-TERM TREATMENT IN PATIENTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA: RESULTS FROM THE COMPOSER TRIAL OPEN-LABEL EXTENSION

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a potentially life-threatening acquired hematopoietic stem-cell disorder, resulting in hematuria, anemia, and acquired thrombophilia. In the Phase I/II COMPOSER trial (NCT03157635), patients (pts) with PNH who were treatment-naive or switched from eculizumab were treated with crovalimab, a novel anti-C5 monoclonal antibody designed with Sequential Monoclonal Antibody Recycling Technology (Röth et al. Blood 2020). Aims: To report the long-term efficacy, safety, pharmacokinetic (PK) and pharmacodynamic (PD) outcomes in pts with PNH treated with crovalimab in the open-label extension (OLE) period of the COMPOSER trial. Methods: COMPOSER consists of four sequential parts followed by an OLE period. Pts with PNH who were treatment-naive or switched from eculizumab in Parts 2, 3, and 4, who completed the primary treatment period through Week 20 and derived benefit from crovalimab treatment, were eligible to enter the OLE (Röth et al. EHA 2019). Long-term efficacy, safety, PK and PD data are presented for the OLE. Efficacy endpoints include change in lactate dehydrogenase (LDH), transfusion avoidance and hemoglobin stabilization (both assessed in 24-week intervals), and breakthrough hemolysis (BTH). PK and PD endpoints include assessment of serum concentrations of crovalimab, complement activity by liposome immunoassay (LIA), and free C5 over time. Results: Overall, 43 of 44 pts entered the OLE and at the clinical cutoff (Nov 1, 2021), 38 pts were ongoing. Mean normalized LDH was maintained at ≤1.5 × upper limit of normal (ULN) during the OLE, and 80% to 100% of evaluable pts achieved LDH ≤1.5 × ULN at each visit (Figure). Transfusion avoidance was achieved in 83% to 92% of pts over each 24-week interval in the OLE. Similarly, hemoglobin stabilization remained relatively stable during the OLE, with 79% to 88% of pts achieving hemoglobin stabilization across 24-week intervals. There was a total of five BTH events during the OLE across all pts (none leading to withdrawal) for an overall BTH rate of 0.05 events per pt-year (95% confidence interval: 0.01, 0.11). The incidence of adverse events (AEs) was reported cumulatively from baseline. Median treatment duration (range) for treatment-naive and switched pts on the study was 3.4 years (0.9-4.4) and 2.9 years (0.4-3.9), respectively. Any grade AEs occurred in 95% (42/44) of pts; none led to withdrawal from treatment. Severe AEs occurred in 17% (3/18) of treatment-naive pts and 19% (5/26) of switched pts. Serious AEs occurred in 32% (14/44) of pts (33% [6/18] in treatment-naive and 31% [8/26] in switched pts), of which 5% (2/44) were assessed as related to study treatment by the investigator. No meningococcal infections or deaths were reported. Crovalimab concentrations were stable and within the expected range over time. Terminal complement activity by LIA was near the lower limit of quantification (10 U/mL) and free C5 levels were maintained at low levels (<0.001 g/L) in most pts. PK/PD relationships between free C5 or LIA with crovalimab confirmed that crovalimab levels of ≈100 μg/mL resulted in complete inhibition of terminal complement activity. Image:Summary/Conclusion: Treatment-naive and switched pts with PNH treated with crovalimab in the COMPOSER trial maintained disease control over long-term follow-up. No new safety signals were identified, and complete terminal complement inhibition was maintained during the OLE. These data support the continued clinical development of crovalimab in PNH.

Opicapone as an Add-on to Levodopa in Patients with Parkinson's Disease Without Motor Fluctuations: Rationale and Design of the PhaseIII, Double-Blind, Randomised, Placebo-Controlled EPSILON Trial.

IntroductionLevodopa remains the cornerstone treatment for Parkinson’s disease (PD) but its use is associated with the development of ‘wearing-off’ fluctuations and other motor and non-motor complications over time. Adding a catechol-O-methyltransferase (COMT) inhibitor to levodopa/dopa decarboxylase (DDC) inhibitor therapy reduces fluctuations in the profile of plasma levodopa levels following oral dosing, and can therefore be beneficial for the management of motor complications. The objective of the EPSILON study is to investigate the efficacy of opicapone (OPC; a third-generation, once-daily COMT inhibitor) in enhancing the clinical benefit of levodopa in patients in earlier stages of PD, without end-of-dose motor fluctuations.MethodsEPSILON is a phase III, double-blind, randomised, placebo-controlled and parallel-group study, designed to evaluate the efficacy and safety of OPC as add-on to levodopa/DDC inhibitor therapy in patients with early PD who do not exhibit signs of motor complications. Eligible patients will be randomised (1:1) to receive OPC 50 mg or placebo, in addition to their existing levodopa/DDC inhibitor therapy, over a 24-week, double-blind treatment period, after which they will have the option of entering an additional 1-year, open-label extension period, during which all patients will receive OPC 50 mg.Planned OutcomesThe primary efficacy endpoints are change in Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) Part III total score from baseline to the end of the double-blind period (double-blind phase) and change in MDS-UPDRS Part IV total score from open-label baseline to the end of the open-label period (open-label phase). Secondary outcomes during the double-blind phase will include other measures of PD symptoms, including quality of life, non-motor symptoms, and development of motor fluctuations. Safety assessments will include evaluation of treatment-emergent adverse events, laboratory safety parameters, suicidality and impulse control disorders.Trial RegistrationEuropean Union Drug Regulating Authorities Clinical Trials Database (number 2020-005011-52).

AB1289 STUDY DESIGN OF A PHASE 2/3 RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY TO ASSESS THE EFFICACY AND SAFETY OF NIPOCALIMAB, AN FcRn ANTAGONIST, IN WARM AUTOIMMUNE HEMOLYTIC ANEMIA (wAIHA)

BackgroundWarm autoimmune hemolytic anemia (wAIHA) is characterized by the destruction of red blood cells (RBCs) by pathogenic autoantibodies which bind to RBCs and lead to their clearance in the spleen and liver. Patients with wAIHA can experience acute worsening of anemia, which can be a medical emergency, and have an increased risk of thromboembolic events and premature death. Nipocalimab is a fully human, aglycosylated, effectorless IgG1 monoclonal antibody that targets the IgG binding site on the neonatal Fc receptor (FcRn) with high affinity. FcRn, which is expressed in endothelial cells, is responsible for recycling IgG into the circulation and for the relatively long half-life of IgG antibodies compared to other Igs. It is expected that nipocalimab, by inhibiting IgG binding to FcRn, will prevent IgG recycling and lower pathogenic IgG autoantibodies that cause many autoimmune diseases including warm autoimmune hemolytic anemia (wAIHA).Nipocalimab has been studied in multiple phase 1 studies in healthy subjects and in a recently completed phase 2 study in subjects with Generalized Myasthenia Gravis (gMG). In the gMG phase 2 study, nipocalimab was well tolerated at doses from 5 mg/kg every 4 weeks to 60 mg/kg every 2 weeks. Treatment with nipocalimab was associated with rapid and durable total serum IgG and pathogenic IgG autoantibody reduction and meaningful clinical response. A statistically significant relationship between IgG autoantibody reduction and clinical benefit was observed. This study provided proof-of-concept evidence that lowering pathogenic IgG autoantibodies can ameliorate the autoimmune condition these antibodies cause.ObjectivesTo share the rationale and study design for an adaptive, phase 2/3 multicenter, randomized, double-blind, placebo-controlled study in patients with wAIHA whose aim is to evaluate the efficacy, safety, tolerability, PK, and PD of nipocalimab compared with placebo1.MethodsMale or female patients ≥18 years of age who have been diagnosed with primary or secondary wAIHA and have not experienced a sufficient response or have not tolerated currently available treatments will be included in the study. Patients with cold antibody AIHA, cold agglutinin syndrome, mixed type (i.e., warm and cold) AIHA, or paroxysmal cold hemoglobinuria will be excluded. Patients will be randomized 1:1:1 to receive nipocalimab at two different dose schedules or placebo. Following completion of 24 weeks of double-blind treatment, patients may enter an open-label extension period to receive nipocalimab.ResultsThe following endpoints will be analyzed:Primary endpoint:Percentage of participants achieving durable response of improvement in hemoglobin (Hgb).Main secondary endpoints:Change from baseline in the total score from the Functional Assessment of Chronic Illness Therapy-Fatigue Scale at the end of the double-blind period.Number of participants who attain normal lactate dehydrogenase, normal haptoglobin, and normal indirect bilirubin levels at a minimum of 3 consecutive visits after baseline.ConclusionA phase 2 study investigating nipocalimab in patients with gMG provided proof of concept for a phase 2/3 interventional study with nipocalimab in patients with wAIHA. This phase 2/3 study is currently enrolling in the USA and Europe.

MO254: Baseline Characteristics of Patients Enrolled in the Ongoing Phase 3 Randomized, Double-Blind, Active-Control Trial of Sparsentan for the Treatment of Focal Segmental Glomerulosclerosis (DUPLEX)

Abstract BACKGROUND AND AIMS Uncontrolled focal segmental glomerulosclerosis (FSGS) often follows a progressive course to end-stage kidney disease and has a profound negative impact on patient quality of life and long-term survival. Treatments that reduce proteinuria and risk of kidney disease progression are urgently needed. Sparsentan is a novel dual endothelin angiotensin receptor antagonist (DEARA) being investigated for FSGS. The Phase 3 DUPLEX study is examining the potential long-term antiproteinuric and nephroprotective potential and safety of sparsentan compared with an active control, angiotensin receptor blocker (ARB) irbesartan in adults and pediatric patients with FSGS. Here we report the baseline characteristics for all patients enrolled in the DUPLEX trial. METHOD DUPLEX is an ongoing, global, Phase 3, multicenter, randomized, double-blind, active-controlled study designed to evaluate the efficacy and safety of sparsentan versus irbesartan in adult and pediatric patients (≥8–75 years old) with FSGS. The study duration is 268 weeks: a 112-week double-blind period followed by an open-label extension period of up to 156 weeks. The primary efficacy endpoint is the slope of eGFR over approximately 2 years of randomized treatment. Key inclusion and exclusion criteria are shown in Table 1. Patients receiving renin–angiotensin–aldosterone system (RAAS) inhibitors underwent a 2-week washout prior to randomization. Patients were randomized 1:1 to sparsentan or irbesartan (target dose 800 and 300 mg/day, respectively), stratified by screening eGFR and urine protein/creatinine ratio (UP/C). The blinded and aggregated baseline characteristics of all patients enrolled in the DUPLEX trial are summarized descriptively. RESULTS The DUPLEX study is fully enrolled with 371 patients (336 adult and 35 pediatric) across 179 study sites in 22 countries. Selected demographic and clinical characteristics in the total population are reported in Table 2. CONCLUSION DUPLEX is the largest randomized controlled trial to date in FSGS. Patients with FSGS enrolled in the DUPLEX trial display demographic and clinical characteristics consistent with the profile previously reported in the broader population of patients globally with FSGS not in remission.

MO209: Baseline Characteristics of Adults Enrolled in the Ongoing Phase 3 Randomized, Double-Blind, Active-Control Trial of Sparsentan For the Treatment of Immunoglobulin A Nephropathy (PROTECT)

Abstract BACKGROUND AND AIMS Immunoglobulin A nephropathy (IgAN) is the most common glomerular disease worldwide. Despite optimized standard of care treatment, up to 40% of individuals with IgAN develop kidney failure requiring dialysis or kidney transplantation, consequently seriously affecting their quality of life and mortality. Treatments that reduce proteinuria and risk of kidney disease progression are urgently needed for IgAN. Sparsentan is a novel Dual Endothelin Angiotensin Receptor Antagonist (DEARA) being investigated for IgAN. The Phase 3 PROTECT study is examining the potential long-term antiproteinuric and nephroprotective potential and safety of sparsentan compared with an active control, angiotensin receptor blocker (ARB) irbesartan, in adults with IgAN. Here we report the baseline characteristics for all patients enrolled in the PROTECT trial. METHOD PROTECT is an ongoing, global, Phase 3, multicenter, randomized, double-blind, parallel-group, active controlled study designed to evaluate the efficacy and safety of sparsentan versus the active control irbesartan in adults with IgAN with overt proteinuria despite receiving maximized treatment with an angiotensin-converting enzyme inhibitor (ACEi) and/or ARB. The study duration is 270 weeks: a double-blind period of 114 weeks followed by an open-label extension period of up to 156 weeks. The primary efficacy endpoint is the change from baseline in urine protein/creatinine ratio (UP/C) based on a 24-h urine sample at Week 36. Key inclusion and exclusion criteria are shown in Table 1. Patients took their last dose of maximized standard-of-care treatment with ACEi and/or ARB therapy the day before randomization. Patients were randomized 1:1 to sparsentan or irbesartan (target dose 400 and 300 mg/day, respectively), stratified by screening eGFR and urine protein excretion values. The blinded and aggregated baseline characteristics of all the patients enrolled in the PROTECT trial are summarized descriptively. RESULTS A total of 406 patients from clinical sites in 18 countries, including sites in North America, Europe and Asia Pacific, were enrolled in PROTECT and 404 patients were included in the primary analysis population. Selected demographic and clinical characteristics are reported in Table 2. CONCLUSION PROTECT is the largest interventional trial testing a novel drug to date in IgAN. Patients with IgAN enrolled in the PROTECT trial display demographic and clinical characteristics consistent with those previously reported in the broader high-risk IgAN patient population. The presentation despite implementation of optimized standard of care treatment demonstrates the burden of IgAN and the unmet need for novel therapies in this patient population.

Phase 3, long-term, open-label extension period of safety and efficacy of belimumab in patients with systemic lupus erythematosus in China, for up to 6 years

ObjectivesTo evaluate the long-term safety and efficacy of belimumab in patients with systemic lupus erythematosus (SLE) in China.MethodsIn this phase 3, open-label extension period, eligible completers of study BEL113750 (NCT01345253)...

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.

P107: A PHASE 2/3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF MITAPIVAT IN PATIENTS WITH SICKLE CELL DISEASE

Background: The key pathology in sickle cell disease (SCD), a life-threatening, hereditary hemoglobin (Hb) disorder, is red blood cell (RBC) sickling due to polymerization of deoxygenated sickle Hb (HbS), which can be exacerbated by increased levels of the glycolytic metabolite 2,3-diphosphoglycerate (2,3-DPG), and decreased ATP.1–3 Sickled RBCs are rigid, not deformable, and fragile, resulting in vaso-occlusion triggering pain and chronic hemolysis.4–6 SCD treatment options are limited, with an unmet need for safe and effective therapies to improve anemia and reduce pain. Mitapivat is an oral, activator of RBC pyruvate kinase (PKR), a key glycolytic enzyme. PKR activation decreases 2,3-DPG and increases ATP, which may reduce HbS polymerization, RBC sickling, and hemolysis in SCD.3,7–9 Data from the phase (ph) 1 National Institutes of Health multiple ascending dose study of up to 100 mg mitapivat twice daily (BID) in SCD (NCT04000165) showed that mitapivat was safe and tolerable, increased ATP and decreased 2,3-DPG in a dose-dependent manner, and improved anemia and hemolysis.8,10 Aims: To report the study design of RISE UP (NCT05031780, EudraCT: 2021-001674-34), a ph 2/3, double-blind, randomized, placebo-controlled, multicenter study evaluating the efficacy and safety of mitapivat in patients (pts) with SCD. Methods: Eligible: pts aged ≥16 yrs with documented SCD (HbSS, HbSC, HbSβ0/HbSβ+ thalassemia, other SCD variants), 2–10 sickle cell pain crises (SCPCs; acute pain needing medical contact, acute chest syndrome, priapism, hepatic or splenic sequestration) in the prior 12 months, and Hb 5.5–10.5 g/dL. If taking hydroxyurea (HU), the dose must be stable for ≥90 days before starting study drug. Ineligible: pts receiving regularly scheduled blood transfusions, with severe kidney disease or hepatobiliary disorders, currently receiving SCD therapies (excluding HU) or who have received gene therapy, bone marrow or stem cell transplantation. In the double-blind ph 2 part, 69 pts will be randomized (1:1:1) to 50 mg or 100 mg mitapivat, or placebo BID for 12 weeks (wks). The primary objective of ph 2 is to determine the recommended ph 3 mitapivat dose by evaluating anemia and safety vs placebo via the following endpoints: Hb response (≥1.0 g/dL increase in average Hb concentration over Wks 10–12 vs baseline [BL]), and type, severity, and relationship of adverse events and serious AEs. In the double-blind ph 3 part, 198 pts who did not participate in ph 2 will be randomized (2:1) to the selected ph 3 mitapivat dose or placebo BID for 52 wks, stratified by number of SCPCs in the prior yr (<5, ≥5) and HU use. The primary objectives of ph 3 are to determine the effect of mitapivat vs placebo on anemia, measured by Hb response (≥1.0 g/dL increase in average Hb concentration over Wks 24–52 vs BL), and the effect of mitapivat vs placebo on SCPC, measured by annualized rate of SCPCs. Key secondary endpoints include average change from BL in Hb concentration, indirect bilirubin, percent reticulocyte, and Pt-Reported Outcomes Measurement Information System® Fatigue 13a Short Form score over Wks 24–52; and annualized frequency of hospitalizations for SCPC. Pts who complete the double-blind period will be eligible to receive mitapivat in the open-label extension period in each ph. Results: Not yet available. Conclusion: This ph 2/3 study will investigate the efficacy and safety of mitapivat in pts aged ≥16 yrs with SCD. Enrollment is currently ongoing.

A randomized, double-blind, placebo-controlled 12-week trial of infliximab in patients with juvenile-onset spondyloarthritis

ObjectiveTo assess the efficacy and safety of infliximab versus placebo in the treatment of patients with juvenile-onset spondyloarthritis (JoSpA).MethodsPhase III, randomized, double-blind, placebo-controlled trial of 12 weeks that included patients ≤ 18 years old with JoSpA not responding to nonsteroidal anti-inflammatory drugs, sulfasalazine, or methotrexate. Patients were randomly assigned 1:1 to the infusion of infliximab 5mg/kg or placebo; completers entered then an open-label extension (OLE) period of 42 weeks. The primary endpoint was the number of active joints. Secondary outcomes included the assessment of disease activity, tender entheses, spinal mobility, serum C-reactive protein (CRP), the Bath Ankylosing Spondylitis Disease Activity and Functional Index, and the Childhood Health Assessment Questionnaire (CHAQ).ResultsWe randomized 12 patients to infliximab and 14 to placebo. No significant differences were found between groups at baseline. At week 12, the mean number of active joints was 1.4 (SD 2.4) in the infliximab group and 4.1 (SD 3.0) in the placebo group (p = 0.0002). A repeated-measures mixed model analysis that included all endpoints in the study demonstrated sustained favourable outcomes of infliximab for active joints, tender joints, swollen joints, and tender enthesis counts, as well as for CHAQ and CRP (p < 0.01). Adverse events were more frequent in the infliximab group, including infections and infusion reactions, but none of them was serious.ConclusionInfliximab is efficacious for patients with JoSpA with an inadequate response to conventional treatment. No serious adverse events with the use of infliximab were observed.

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.

Safety of Ocrelizumab in Patients With Relapsing and Primary Progressive Multiple Sclerosis.

Background and ObjectivesTo report safety of ocrelizumab (OCR) up to 7 years in patients with relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS) enrolled in clinical trials or treated in real-world postmarketing settings.MethodsSafety analyses are based on integrated clinical and laboratory data for all patients who received OCR in 11 clinical trials, including the controlled treatment and open-label extension (OLE) periods of the phase 2 and 3 trials, plus the phase 3b trials VELOCE, CHORDS, CASTING, OBOE, ENSEMBLE, CONSONANCE, and LIBERTO. For selected adverse events (AEs), additional postmarketing data were used. Incidence rates of serious infections (SIs) and malignancies were contextualized using multiple epidemiologic sources.ResultsAt data cutoff (January 2020), 5,680 patients with multiple sclerosis (MS) received OCR (18,218 patient-years [PY] of exposure) in clinical trials. Rates per 100 PY (95% confidence interval) of AEs (248; 246–251), serious AEs (7.3; 7.0–7.7), infusion-related reactions (25.9; 25.1–26.6), and infections (76.2; 74.9–77.4) were similar to those within the controlled treatment period of the phase 3 trials. Rates of the most common serious AEs, including SIs (2.01; 1.81–2.23) and malignancies (0.46; 0.37–0.57), were consistent with the ranges reported in epidemiologic data.DiscussionContinuous administration of OCR for up to 7 years in clinical trials, as well as its broader use for more than 3 years in the real-world setting, are associated with a favorable and manageable safety profile, without emerging safety concerns, in a heterogeneous MS population.Classification of EvidenceThis analysis provides Class III evidence that long-term, continuous treatment with OCR has a consistent and favorable safety profile in patients with RMS and PPMS. This study is rated Class III because of the use of OLE data and historical controls.

Duration and onset of effect of incobotulinumtoxinA for the treatment of blepharospasm in botulinum toxin-naïve subjects

Objective Blepharospasm is a focal dystonia whereby excessive eyelid muscle contractions cause involuntary eye closure. Botulinum neurotoxin type A (BoNT-A) injections are an approved treatment. This randomized placebo-controlled trial (NCT01896895; EudraCT number 2012-004821-26) assessed the efficacy, safety, and treatment effect duration of incobotulinumtoxinA (Xeomin, Merz Pharmaceuticals GmbH), a BoNT-A formulation without complexing proteins, in BoNT-A-naïve adults with blepharospasm. Methods Subjects received incobotulinumtoxinA 50 U, 25 U (total dose) or placebo during a main study period (MP; 6–20 weeks). Patients needing a second injection received incobotulinumtoxinA ≤70 U in an open-label extension period (EP; 6–20 weeks). Treatment effect durations were time from first injection to EP injection or final MP visit and from EP injection to end-of-study visit. Times to effect onset and to waning of effect (MP) were time from injection to first subject-assessed onset effect and time from injection to subject-reported waning of effect, respectively. Results Of 61 subjects, 39 entered the EP. During the MP, median duration of treatment effect was longer with incobotulinumtoxinA 50 U (20 weeks) versus incobotulinumtoxinA 25 U (11 weeks) or placebo (6 weeks). Median duration of treatment effect was 20 weeks during the EP. Median time to effect onset was 5, 7, and 14 days with 50 U, 25 U, and placebo, respectively (p = .022 for 50 U versus placebo). Median time to waning of treatment effect was comparable between groups. Conclusion Subjects reported an effect onset from 5 days after injection lasting up to 20 weeks (maximum observation period). Data indicate that incobotulinumtoxinA re-treatment of blepharospasm may not be required at fixed 12-week intervals and provide evidence for a patient-tailored approach.

Placebo-Controlled Clinical Trial of IncobotulinumtoxinA for Sialorrhea in Children: SIPEXI.

Background and ObjectivesTo investigate the efficacy and safety of repeated injections of incobotulinumtoxinA (incoBoNT/A) for treatment of chronic sialorrhea (drooling) associated with neurologic disorders (e.g., cerebral palsy, traumatic brain injury) or intellectual disability in children and adolescents in a prospective phase III study (SIPEXI [Sialorrhea Pediatric Xeomin Investigation]).MethodsThe study enrolled 2- to 17-year-old patients with sialorrhea due to neurologic disorders or intellectual disability. Patients received body weight–dependent doses of incoBoNT/A (20–75 U). A main period with 1 injection cycle (placebo-controlled, double-blind, 6- to 17-year-olds) was followed by an open-label extension with up to 3 further cycles. An additional cohort of 2- to 5-year-olds received active treatment throughout the study. Coprimary endpoints were the change in unstimulated salivary flow rate (uSFR) from baseline to week 4 and the carers' Global Impression of Change Scale (GICS) rating at week 4. Adverse events were recorded.ResultsIn the main period, 220 patients aged 6–17 years were randomized and treated (148 patients in incoBoNT/A group, 72 patients in placebo group). A total of 35 patients aged 2–5 years received incoBoNT/A (no placebo). A total of 214 patients aged 6–17 years and 33 patients aged 2–5 years continued treatment in the open-label extension period. For the 6- to 17-year-olds, a significant difference between incoBoNT/A and placebo was seen in mean uSFR decrease (difference −0.06 g/min; p = 0.0012) and the carers' GICS rating (difference 0.28 points; p = 0.032) at week 4, in favor of active treatment. The secondary endpoints consistently supported these results. A sustained benefit was observed during the extension. Incidences of adverse events were comparable between incoBoNT/A and placebo and did not increase notably with repeated injections. The most common adverse events were respiratory infections. Efficacy and safety were also favorable in the uncontrolled cohort of 2- to 5-year-olds.DiscussionBoth co–primary efficacy endpoints were reached and superiority of incoBoNT/A over placebo was confirmed. IncoBoNT/A (up to 75 U, up to 4 cycles) is an effective and well-tolerated treatment for sialorrhea associated with neurologic disorders in children.Trial Registration InformationClinicaltrials.gov: NCT02270736 (clinicaltrials.gov/ct2/show/results/NCT02270736); EU Clinical Trials Register: 2013-004532-30 (clinicaltrialsregister.eu/ctr-search/search?query=2013-004532-30).Classification of EvidenceThis study provides Class I evidence that injection of incobotulinumtoxinA decreases drooling in children aged 6 to 17 years with neurologic disorders.