Sustained Clinical Efficacy Research Articles

Long-term efficacy and safety of secukinumab in patients with moderate-to-severe hidradenitis suppurativa: Week 104 results from the SUNSHINE and SUNRISE extension trial.

SUNSHINE and SUNRISE demonstrated sustained clinical efficacy of secukinumab in patients with moderate-to-severe hidradenitis suppurativa (HS) through 52 weeks. Patients completing the core trials could enter a 4-year extension trial. To evaluate the long-term efficacy, safety/tolerability, and maintenance of clinical response of secukinumab through Week 104 in the extension trial. Patients with a HS clinical response (HiSCR) at Week 52 of the core trials (extension trial baseline visit) entered a randomised withdrawal period. HiSCR responders receiving subcutaneous (s.c.) secukinumab 300 mg every 2/4 weeks (SECQ2W/SECQ4W) through Week 52 in the core trials were randomised 2:1 to continue secukinumab (SECQ2W-R-Q2W or SECQ4W-R-Q4W) or receive placebo (SECQ2W-R-PBO or SECQ4W-R-PBO) through Week 104. The primary endpoint was time to loss of response (LOR; newly-defined for this trial) through Week 104 in Week 52 HiSCR responders (SECQ2W-R-Q2W vs. SECQ2W-R-PBO and SECQ4W-R-Q4W vs. SECQ4W-R-PBO). Time to LOR was tested at 1.25% (one-sided) for each comparison (one-sided familywise alpha of 2.5%) through Week 104. If LOR was met, patients could remain in the trial on open-label secukinumab treatment. Additional endpoints included safety and HiSCR. Overall, 84.3% of patients completing the core trials entered the extension trial; 55.9% were Week 52 HiSCR responders. The primary endpoint was not met for either secukinumab dosing regimen. The estimated risk reduction for LOR was 13% (SECQ2W-R-Q2W vs. SECQ2W-R-PBO; one-sided P=0.250) and 30% (SECQ4W-R-Q4W vs. SECQ4W-R-PBO; one-sided P=0.044). The median time to LOR was numerically longer in secukinumab arms versus placebo (SECQ2W-R-Q2W [283 days; 95% CI: 176, -] vs. SECQ2W-R-PBO [239 days; 95% CI: 120, -]; SECQ4W-R-Q4W [365 days 95% CI: 225, -] vs. SECQ4W-R-PBO [171 days; 95% CI: 113, 337]). In Week 52 HiSCR responders reporting LOR, 43.8% (SECQ2W-R-Q2W), 57.5% (SECQ2W-R-PBO), 39.7% (SECQ4W-R-Q4W) and 34.1% (SECQ4W-R-PBO) were achieving HiSCR at the time of LOR. Overall, the safety of secukinumab was consistent with the core trials. The primary endpoint of this trial was not met. HiSCR was maintained in many patients at the time of LOR. The safety of secukinumab was consistent with the previously characterised safety profile in the core trials. Clinicaltrials.gov ID NCT04179175.

Bimekizumab Efficacy and Safety in Patients With Psoriatic Arthritis Who Had Skin and Nail Psoriasis at Baseline: Up to 2-year Results From Two Phase 3 Studies

Introduction: Bimekizumab (BKZ), a humanized anti-IL17F anti-IL17A antibody has demonstrated efficacy and tolerability to 1 year in patients with psoriatic arthritis (PsA) and psoriasis.1 Nail psoriasis is associated with increased PsA risk, more severe disease and decreased quality of life, in patients with psoriasis.2,3 Here, efficacy and safety of BKZ treatment are reported to 2 years in patients with PsA, skin involvement and nail psoriasis in two phase 3 trials. Methods: BE OPTIMAL (NCT03895203; bDMARD-naïve) and BE COMPLETE (NCT03896581; TNFi‑IR) assessed subcutaneous BKZ 160 mg Q4W in patients with PsA. Placebo (PBO) patients switched to BKZ (PBO/BKZ) at Wk16. BE OPTIMAL included a reference arm (adalimumab [ADA] 40 mg Q2W); ADA patients switched to BKZ at Wk52 (ADA/BKZ). BE OPTIMAL Wk52 and BE COMPLETE Wk16 completers could enter BE VITAL (open-label extension; NCT04009499), where all patients received BKZ. Post-hoc data reported for patients with baseline skin involvement (≥3% body surface area) and nail psoriasis (modified Nail Psoriasis Severity Index >0). Efficacy reported to Wk104 of BE OPTIMAL/Wk100 of BE COMPLETE. Missing data imputed using non‑responder, multiple or worst-category imputation. Safety data are reported for all patients treated with BKZ. Results: Of 263/852 (30.9%) bDMARD-naïve and 159/400 (39.8%) TNFi-IR patients with baseline skin and nail psoriasis, 230 (87.5%) and 136 (85.5%) patients completed Wk104/Wk100. Efficacy responses at Wk52 on BKZ were sustained to Wk104/Wk100 across joint, skin, nail, physical function and composite outcomes. ADA/BKZ cohort showed sustained responses after switch. For bDMARD-naïve and TNFi-IR patients on BKZ, the exposure-adjusted incidence rates per 100 patient-years (EAIR/100 PY) for ≥1 treatment-emergent adverse event (TEAE) were 154.9 and 78.8, respectively; and for serious TEAEs, 6.6 and 5.2 respectively. None of the reported Candida infections were serious or systemic; all 3 deaths were deemed unrelated to treatment. Conclusions: BKZ treatment demonstrated sustained clinical efficacy to 2 years in patients with PsA, skin involvement and nail psoriasis, regardless of prior TNFi treatment. BKZ was well tolerated; consistent safety profile to previous reports.1

Safety and Efficacy of Bimekizumab in Patients with Psoriatic Arthritis: 2-Year Results from Two Phase 3 Studies.

Psoriatic arthritis (PsA) is a chronic inflammatory disease requiring long-term treatment. Bimekizumab, a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A, has demonstrated tolerability and sustained clinical efficacy for up to 1year for patients with PsA. Here, we report the longer-‍term safety and efficacy of bimekizumab up to 2years. BE OPTIMAL (biologic disease-modifying antirheumatic drug [bDMARD]-naïve) and BE COMPLETE (prior inadequate response/intolerance to tumor necrosis factor inhibitors [TNFi-IR]) assessed subcutaneous bimekizumab 160mg every 4weeks in patients with PsA. BE OPTIMAL included a reference arm (adalimumab 40mg every 2weeks); patients switched to bimekizumab at week 52 with no washout between treatments. BE OPTIMAL week 52 and BE COMPLETE week 16 completers were eligible for the BE VITAL open-label extension. Efficacy outcomes are reported to week 104/100 (BE OPTIMAL/BE COMPLETE). A total of 710/852 (83.3%) bDMARD-naïve and 322/400 (80.5%) TNFi-IR patients completed week 104/100. Up to 104weeks, patients treated with bimekizumab in BE OPTIMAL and BE COMPLETE had treatment-emergent adverse event incidence rates (exposure-adjusted incidence rate/100 patient-years) of 179.9 (95% CI 166.9, 193.7) and 100.3 (89.2, ‍112.4), respectively. The proportion of patients achieving efficacy outcomes (≥ 50% improvement from baseline in American College of Rheumatology [ACR] response criteria, 100% improvement from baseline in Psorisis Area and Severity Index [PASI], minimal disease activity [MDA]) was sustained in all patients from week 52 to week 104/100. Bimekizumab was well tolerated for up to 2years of treatment and no new safety signals were observed. Sustained clinical efficacy was observed up to 2years in bDMARD-naïve and TNFi-IR patients with active PsA. Patients switching from adalimumab to bimekizumab demonstrated further improvement in skin and nail symptoms, and sustained efficacy in joint symptoms. BE OPTIMAL (NCT03895203), BE COMPLETE (NCT03896581), BE VITAL (NCT04009499).

Complete response using the EZH2 inhibitor tazemetostat against multiple relapsed follicular lymphoma in the leukemic phase.

Though multiple relapses and serial shortening of remission is one of the characteristics of follicular lymphoma (FL), standard third- and later-line treatments with clear evidence have not yet been established. Tazemetostat, the first oral enhancer of zester homolog 2 (EZH2) inhibitor, showed a favorable clinical outcome and safety profile against relapsed mutant EZH2 FL in a clinical trial and was applied to this clinical setting. Peripheral blood involvement, known as the leukemic phase, was observed in approximately 10% of patients with FL and reported as a poor prognostic factor. However, because of the infrequency of EZH2-activating mutations, clinical data on tazemetostat against FL in the leukemic phase is lacking. Herein, we report a case of multiple relapsed FL in the leukemic phase for which tazemetostat was administered as a sixth-line treatment. Tazemetostat monotherapy showed a slow and sustained clinical efficacy in the leukemic phase as shown by nodal involvement. Circulating lymphoma cells gradually decreased and disappeared in counts after 4months of treatment. However, circulating lymphoma cells were still detected by flow cytometry up to 6months of treatment and finally undetected after 9months. Extended-interval dosing of tazemetostat transformed a partial response into a complete response. Thus, tazemetostat is effective for the treatment of multiple relapsed FL in the leukemic phase.

Structural design of the anti-TNFα therapeutic NANOBODY® compound, ozoralizumab, to support its potent and sustained clinical efficacy

Structural design of the anti-TNFα therapeutic NANOBODY® compound, ozoralizumab, to support its potent and sustained clinical efficacy

A systematic review and meta-analysis assessing the efficacy of Tuina for nocturnal enuresis in children.

Background: Desmopressin acetate (DDAVP) and behavioral interventions (BI) are cornerstone treatments for nocturnal enuresis (NE), a common pediatric urinary disorder. Despite the growing body of clinical studies on massage therapy for NE, comprehensive evaluations comparing the effectiveness of Tuina with DDAVP or BI are scarce. This study aims to explore the efficacy of Tuina in the management of NE. Methods: A systematic search of international databases was conducted using keywords pertinent to Tuina and NE. The inclusion criteria were limited to randomized controlled trials (RCTs) that evaluated NE treatments utilizing Tuina against DDAVP or BI. This meta-analysis included nine RCTs, comprising a total of 685 children, to assess both complete and partial response rates. Results: Tuina, used as a combination therapy, showed enhanced clinical efficacy and improved long-term outcomes relative to the control group. The therapeutic efficacy of Tuina was not directly associated with the number of acupoints used. Instead, employing between 11 and 20 acupoints appeared to have the most significant effect. Conclusion: The findings of this meta-analysis support the potential of Tuina as an adjunct therapy to enhance the sustained clinical efficacy of traditional treatments for NE. However, Tuina cannot completely replace DDAVP or BI in the management of NE. While this study illuminates some aspects of the effective acupoint combinations, further research is crucial to fully understand how Tuina acupoints contribute to the treatment of NE in children. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=442644, identifier CRD42023442644.

Safety and Efficacy of Radiosynoviorthesis: A Prospective Canadian Multicenter Study.

Radiosynoviorthesis is approved in several European countries and the United States to treat refractory synovitis in many inflammatory joint diseases, such as rheumatoid arthritis, spondyloarthropathies, and other arthritic joint diseases. No radiopharmaceuticals for radiosynoviorthesis are currently approved in Canada. The aim of this Health Canada-approved trial was to demonstrate the safety and efficacy of radiosynoviorthesis. Methods: Between July 2012 and November 2017, we conducted a multicenter, prospective, interventional Canadian trial. Patients (n = 360) with synovitis refractory to standard treatments after failing 2 intraarticular glucocorticoid injections were included. They were followed up at 3, 6, and 12 mo. Outcome measures included adverse events (AEs) and clinical signs of synovitis (pain, swelling, and joint effusion) measured with the Health Assessment Questionnaire Disability Index, the Disease Activity Score, and the Visual Analog Scale. Results: In total, 392 joints were treated, including those reinjected after 6 mo (n = 34). Of these, 83.4% (327/392) were injected with [90Y]Y-citrate for the knees and 9.9% (39/392) with [186Re]Re-sulfide for medium-sized joints. Of the joints treated, 82.7% (324/392) were knees. Fifty-five AEs, most of them of mild grade, occurred and resolved without sequelae and were not life-threatening. The incidence of radiosynoviorthesis-related AEs was 9.4% (34/360). The proportion of patients showing an improvement in synovitis symptoms after radiosynoviorthesis was significant at 3 mo and was maintained up to 12 mo (P < 0.001). Conclusion: This study confirmed the safety of radiosynoviorthesis in the treatment of patients with synovitis refractory to standard treatments. There is evidence of sustained clinical efficacy at 12 mo, suggesting that radiosynoviorthesis is an effective treatment for improving synovitis symptoms.

3-year clinical outcomes of A Singapore VenaSeal™ real world post-market evaluation Study (ASVS) for varicose vein ablation

IntroductionMedium-term clinical outcome data are lacking for cyanoacrylate glue (CAG) ablation for symptomatic varicose veins, especially from the Asian population.ObjectivesAim was to determine the 3-year symptomatic relief gained from using the VenaSeal™ device to close refluxing truncal veins from the Singaporean ASVS prospective registry.MethodsThe revised Venous Clinical Severity Score (rVCSS) and three quality of life (QoL) questionnaires were completed to assess clinical improvement in venous disease symptoms along with a dedicated patient satisfaction survey. 70 patients (107 limbs; 40 females; mean age of 60.9 ± 13.6 years) were included at 3 years.ResultsAt 3 years, rVCSS showed sustained improvement from baseline (5.00 to 0.00; p < 0.001) and 51/70 (72.9%) had improvement by at least 2 or more CEAP categories.Freedom from reintervention was 90% and 85.7% patients were extremely satisfied with the treatment outcome. No further reports of further hypersensitivity reactions after one year.ConclusionThe 3-year follow-up results of the ASVS registry demonstrated continued and sustained clinical efficacy with few reinterventions following CAG embolization in Asian patients with chronic venous insufficiency.Trial registrationClinicalTrials.gov Registration: NCT03893201.

Neutralizing IgG4 antibodies are a biomarker of sustained efficacy after peanut oral immunotherapy

BackgroundClinical efficacy of oral immunotherapy (OIT) has been associated with the induction of blocking antibodies, particularly those capable of disrupting IgE-allergen interactions. Previously, we identified monoclonal antibodies (mAb) to Ara h 2 and structurally characterized their epitopes. ObjectiveWe investigated longitudinal changes during OIT in antibody binding to conformational epitopes and correlated the results with isotype and clinical efficacy. MethodsWe developed an indirect inhibitory ELISA using mAbs to block conformational epitopes on immobilized Ara h 2 from binding to serum immunoglobulins from peanut-allergic patients undergoing OIT. We tested the functional blocking ability of mAbs using passive cutaneous anaphylaxis (PCA) in mice with humanized FcεRI receptors. ResultsDiverse serum IgE recognition of Ara h 2 conformational epitopes are similar before and after OIT. Optimal inhibition of serum IgE occurs with the combination of two neutralizing mAbs (nAbs) recognizing epitopes 1.2 and 3, compared to two non-neutralizing mAbs (non-nAbs). Post-OIT, IgG4 nAbs, but not IgG1 or IgG2 nAbs, increased in sustained compared to transient outcomes. Induction of IgG4 nAbs occurs after OIT only in those with sustained efficacy. Murine PCA after sensitization with pooled human sera is significantly inhibited by nAbs compared to non-nAbs. ConclusionsSerum IgE conformational epitope diversity remains unchanged during OIT. However, IgG4 nAbs capable of uniquely disrupting IgE-allergen interactions to prevent effector cell activation are selectively induced in OIT-treated individuals with sustained clinical efficacy. Therefore, the induction of neutralizing IgG4 antibodies to Ara h 2 are clinically relevant biomarkers of durable efficacy in OIT.

Real-World Outcomes of Crizotinib in ROS1-Rearranged Advanced Non-Small-Cell Lung Cancer

Real-world data on the use and outcomes of crizotinib in ROS1-rearranged non-small-cell lung cancer (NSCLC) are limited. This study aims to analyze the real-world efficacy of crizotinib in South Korea and explore the utilization of liquid biopsies that implement next-generation sequencing (NGS) using cell-free total nucleic acids. In this prospective multicenter cohort study, 40 patients with ROS1-rearranged NSCLC, either starting or already on crizotinib, were enrolled. Patients had a median age of 61 years, with 32.5% presenting brain/central nervous system (CNS) metastases at treatment initiation. At the data cutoff, 48.0% were still in treatment; four continued with it even after disease progression due to the clinical benefits. The objective response rate was 70.0%, with a median duration of response of 27.8 months. The median progression-free survival was 24.1 months, while the median overall survival was not reached. Adverse events occurred in 90.0% of patients, primarily with elevated transaminases, yet these were mostly manageable. The NGS assay detected a CD74–ROS1 fusion in 2 of the 14 patients at treatment initiation and identified emerging mutations, such as ROS1 G2032R, ROS1 D2033N, and KRAS G12D, during disease progression. These findings confirm crizotinib’s sustained clinical efficacy and safety in a real-world context, which was characterized by a higher elderly population and higher rates of brain/CNS metastases. The study highlights the clinical relevance of liquid biopsy for detecting resistance mechanisms, suggesting its value in personalized treatment strategies.

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

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

Long-Term Efficacy and Safety of Elranatamab Monotherapy in the Phase 2 Magnetismm-3 Trial in Relapsed or Refractory Multiple Myeloma (RRMM)

BACKGROUND Elranatamab is a humanized, bispecific antibody that targets B-cell maturation antigen (BCMA) on myeloma cells and CD3 on T cells, with the aim of inducing T-cell-mediated cytolysis of the myeloma cells. In the MagnetisMM-3 (NCT04649359) trial, an open-label, multicenter, non-randomized, phase 2 registrational study of elranatamab monotherapy, patients with RRMM who had not received prior BCMA-directed therapy (ie, BCMA-naïve patients; n=123) achieved objective responses with an overall response rate (ORR) of 61%. Here, we report the long-term efficacy and safety of elranatamab. METHODS Eligible patients had previously received at least 1 proteasome inhibitor, 1 immunomodulatory drug, and 1 anti-CD38 antibody. Patients received step-up doses of 12 and 32 mg elranatamab subcutaneously on days 1 and 4 of cycle 1, respectively, followed by 76 mg elranatamab once-weekly (QW), starting on day 8 of the first 4-week cycle. Patients who received ≥6 months of QW dosing and achieved ≥ partial response lasting at least 2 months were transitioned to a once every 2 weeks (Q2W) dosing schedule and from Q2W to once every 4 weeks after at least 6 Q2W cycles. Treatment with elranatamab continued until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was ORR, assessed by blinded-central review per International Myeloma Working Group criteria. Minimal residual disease (MRD) status was assessed using next-generation sequencing, with MRD negativity defined as &amp;lt;1 myeloma cell in 10 5 nucleated cells. Adverse events were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) severity were graded by American Society for Transplantation and Cellular Therapy criteria. RESULTS After a median follow-up of 15.9 months (data cutoff, April 16, 2023), 32.5% of patients remained on treatment. The confirmed ORR was 61.0% (n=123; 95% CI, 51.8-69.6), with 35.8% of patients achieving complete responses (CR) or better. Among evaluable patients (those with ≥CR and evaluable for MRD, n=29), 89.7% achieved MRD negativity. Median duration of response (DOR), progression-free survival (PFS), and overall survival (OS) have not been reached, and the probabilities of maintaining a response, being progression-free, and being alive at 15 months were 70.8% (95% CI, 58.2-80.2), 50.2% (95% CI, 40.2-59.3), and 56.3% (95% CI, 47.0-64.6), respectively. All participants (100%) had ≥1 any grade treatment-emergent adverse events (TEAEs), and 70.7% of patients had grade 3/4 TEAEs. The most common any grade (≥25%) and grade 3/4 (≥10%) adverse events (any grade, grade 3/4) were infections (69.9%, 40.7%), CRS (57.7%, 0%), anemia (48.8%, 37.4%), neutropenia (48.8%, 48.8%), diarrhea (41.5%, 1.6%) thrombocytopenia (31.7%, 23.6%), lymphopenia (26.8%, 25.2%), fatigue (36.6%, 4.1%), nausea (26.8%, 0%), injection site reaction (26.8%, 0%), hypokalemia (26.0%, 10.6%), cough (26.0%, 0%) pyrexia (30.9%, 4.1%), decreased appetite (33.3%, 0.8%), leukopenia (15.4%, 13.0%) and COVID-19 pneumonia (14.6%, 11.4%). CONCLUSIONS Extended follow-up from the ongoing phase 2 MagnetisMM-3 trial of elranatamab in heavily pretreated participants with RRMM demonstrated sustained clinical efficacy, with median DOR, PFS, and OS not reached, and no new safety signals.

Effects of secukinumab on synovitis and enthesitis in patients with psoriatic arthritis: 52-week clinical and ultrasound results from the randomised, double-blind ULTIMATE trial with open label extension

ObjectivesIn the ULTIMATE study with an open label extension, we assessed the long-term effect of secukinumab at tissue level on synovitis and enthesitis, and across all psoriatic arthritis (PsA) manifestations, using both clinical evaluations and power Doppler ultrasonography (PDUS). MethodsThis randomised, placebo-controlled, Phase 3 study (ULTIMATE) included biologic-naïve patients with PsA with active PDUS synovitis and clinical enthesitis, and inadequate response to conventional synthetic disease-modifying antirheumatic drugs. The study consisted of 3 treatment periods; in the first period (baseline to week 12) patients were randomised to receive subcutaneous secukinumab (150 mg or 300 mg according to severity of skin psoriasis) or placebo every week until week 4 and once every 4 weeks up to week 12. In the second period (weeks 12–24) all patients received open-label secukinumab with placebo patients switching to secukinumab (150 mg or 300 mg). The third period (weeks 24–52) was an extended open-label treatment period. The long-term responsiveness of the Global EULAR-OMERACT Synovitis Score (GLOESS), clinical enthesitis and global PDUS-detected enthesitis score (using two candidate definitions of activity) at patient level, together with clinical efficacy across key manifestations of PsA and safety were assessed. ResultsOf the 166 patients enrolled, 144 completed week 52. A significant reduction in GLOESS was demonstrated in the secukinumab group vs placebo at week 12, followed by a stable reduction of synovitis until week 52 in the secukinumab group while placebo switchers from week 12 reached a similar level of reduction at week 24 with stability thereafter. Likewise, a significant reduction in the Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis index was shown in the secukinumab group vs placebo at week 12 with sustained improvement to week 52. Global OMERACT PDUS enthesitis scores were numerically lower in secukinumab vs placebo switchers in the first two treatment periods, with some stability in the third period in both groups. Improvements in clinical responses were also observed across all key domains of PsA up to week 52 in both treatment groups with no new or unexpected safety signals. ConclusionsULTIMATE showed consistent improvements in clinically and ultrasound-assessed synovitis and enthesitis and sustained clinical efficacy through week 52 in patients with PsA treated with secukinumab and placebo switched to secukinumab.

Long-Term Efficacy and Safety of L-Glutamine in Preventing Sickle Cell Disease-Related Acute Complications and Hemolysis in Pediatric and Adult Patients: A Real-World Observational Study

Introduction: L-glutamine plays an important role in regulating oxidative stress, one of the key contributors to sickle cell disease pathophysiology. An earlier 48-week Phase 3 study conducted in the United States demonstrated significant reductions in acute complications associated with sickle cell disease, such as vaso-occlusive crises (VOCs) and acute chest syndrome (ACS) in patients on L-glutamine therapy compared to those on placebo (Niihara et al., 2018). This study also showed a significantly fewer number of hospitalizations and hospitalization days for those treated with L-glutamine. Our current real-world observational study is the first to report long term evaluation (120 weeks) of efficacy and safety of L-glutamine (Endari®) therapy in patients living with sickle cell disease in Qatar and French Guiana. Methods: Nineteen patients (10 pediatric and 9 adults), 63% on hydroxyurea, with confirmed diagnosis of sickle cell disease (HbSS genotype) were treated with L-glutamine oral powder (~0.3 g/kg body weight) twice daily for 120 weeks. Of the enrolled patients, 4 patients were from Qatar with the Arab-Indian haplotype and 15 patients were from French Guiana with the African haplotype. The median age was 17 years (range 8 to 54 years) where 53% were <18 years of age. The median body weight of patients was 50 kilograms (range of 25 to 75 kilograms); 53% were males. Clinical events and laboratory parameters (hemoglobin, hematocrit, reticulocytes, and LDH) were collected or measured at baseline, 24, 48, 72, 96, and at 120 weeks. Baseline measures for VOCs, number of hospitalizations, hospitalization days, ACS events, and blood transfusions were collected for the 12 months prior to L-glutamine initiation. Changes from baseline to 120 weeks (annualized) were analysed using MedCalc statistical software Version 20.015. Results: Eighteen patients completed 120 weeks of the real-world L-glutamine treatment observation period. There were significantly fewer VOCs; median of 3 VOCs at baseline and median of 0 at 120 weeks. There were significantly fewer hospitalizations (median of 3 hospitalizations at baseline and 0 at 120 weeks), shorter hospitalization days (median of 15 days at baseline and 0 at end of the observation period), and fewer blood transfusions (median of 3 at baseline and 0 at 120 weeks). The change from baseline values to 120 weeks were significant (p < .00001) for VOCs, hospitalizations, days hospitalized, and the number of units transfused. The number of ACS events were also reduced from 11 at baseline to 0 at 120 weeks. Consistent with these findings, the mean increase in hemoglobin concentrations from baseline was 1.36 g/dL ± 0.17 SE and the mean percent increase in hematocrit from baseline was 5.85% ± 1.10 SE, both significantly improved at 120 weeks (p < .001) Figure 1A. Furthermore, mean reticulocyte counts decreased from baseline (-52.39 x 109/L ± 25.68 SE) and LDH levels decreased from baseline (-311.11 U/L ± 56.02 SE) both significantly changed at 120 weeks (p < .001) Figure 1B. Fewer number of patients were taking hydroxyurea at 120 weeks (8 patients) compared to baseline (12 patients). One patient died during the study (after the 72-week follow up visit) due to multiple deep vein thromboses resulting in a pulmonary embolism; this event was not related to L-glutamine treatment. Conclusion: In this long-term observational study, oral L-glutamine therapy in pediatric and adults living with sickle cell disease resulted in sustained clinical efficacy with improvements in hematologic parameters. L-glutamine therapy was well-tolerated by all patients and there were no safety concerns. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Comparing the efficacy and safety of two different drug-coated balloons in in-stent restenosis: Two-year clinical outcomes of the RESTORE ISR China randomized trial

BackgroundThis head-to-head, multicenter, randomized trial investigated the safety and efficacy of Restore (Cardionovum, Bonn, Germany) drug-coated balloon (DCB) angioplasty in an Asian patient population with coronary drug-eluting stent in-stent restenosis (DES-ISR). MethodsA total of 240 patients with coronary DES-ISR were treated with Restore DCB or with SeQuent® Please (Braun, Melsungen, Germany) DCB. This trial used nine-month in-segment late lumen loss (LL) as the primary endpoint. Secondary endpoints included two-year clinical event rates. ResultsPatient, lesion, and procedural characteristics in both treatment groups were similar. Nine-month in-segment LL was 0.38 ± 0.50 mm with Restore vs. 0.35 ± 0.47 mm with SeQuent® Please (p for non-inferiority = 0.02). The two-year follow-up rates were 95.8 % (115/120) in the Restore group and 94.2 % (113/120) in the SeQuent® Please group. Both groups had similar one- and two-year target lesion failure (TLF) rates (13.3 % vs. 12.6 %; p = 0.87 at one year, 14.8 % vs. 15.0 %; p = 1.0 at two years). Moreover, the all-cause mortality and myocardial infarction rates were 0 and 3.5 % (4/120) in the Restore group and 0.9 % (1/120) and 3.5 % (4/120) in the SeQuent® Please group, respectively. Additional analyzing of vessel quantitative flow ratio (QFR) did also show noninferior outcomes for one explicit treatment bunch. ConclusionsThe two-year follow-up indicated sustained long-term clinical safety and efficacy for both devices on the basis of QFR value.

Hypothesis: Bolus jejunal feeding via an enteral feeding tube simulates key features of gastric bypass to initiate similar clinical benefits

BackgroundTherapy for obesity and related comorbidities should be clinically effective, widely available and acceptable, and used in conjunction with an optimized lifestyle. Dieting is widely available and acceptable but has poorly sustained clinical efficacy. By contrast, Roux-en-Y gastric bypass (GB) is highly effective but cost and safety concerns limit widespread use. In this article this we discuss the hypothesis that bolus jejunal feeding (BJ) via an enteral feeding tube simulates key features of GB with the potential for similar clinical benefits. We further hypothesize that a practical manner of providing BJ therapeutically is via an externally inapparent orojejunal feeding tube. RationaleThe first hypothesis is underpinned by the outcomes of research in three fields: 1) investigations into the mechanisms underlying the benefit of GB, 2) studies investigating gastrointestinal physiology and pathophysiology using enteral feeding tubes, and3) investigations into the mechanism underlying involuntary anorexia and weight loss in clinical situations that entail rapid nutrient delivery to the jejunum. There is compelling evidence that a supraphysiologic rate of delivery of nutrient to the jejunum suppresses appetite and energy intake and improves glucose homeostasis, and that these effects can be achieved non-surgically using an enteral feeding tube. The second hypothesis is supported by clinical demonstration of the feasibility of administering intermittent cycles of bolus feeds via an intraorally anchored feeding tube in ambulatory obese adults. ConclusionThe hypotheses are testable in clinical studies. If validated, BJ could be used to induce the clinical benefits of GB, but without its costs or safety concerns.

Eculizumab Pharmacokinetics and Pharmacodynamics in Patients With Generalized Myasthenia Gravis.

Objective: To investigate the pharmacokinetics, pharmacodynamics, and exposure–response of the approved 900/1,200 mg dosing regimen for the terminal complement component 5 (C5) inhibitor eculizumab in patients with generalized myasthenia gravis (gMG).Methods: The analysis used data from 62 patients aged ≥ 18 years with anti-acetylcholine receptor (AChR) antibody-positive refractory gMG who received eculizumab during the REGAIN study (ClinicalTrials.gov: NCT01997229). One- and two-compartment population-pharmacokinetic models were evaluated, and the impact of covariates on pharmacokinetic parameters was assessed. Relationships between eculizumab exposure and free C5 concentration, in vitro hemolytic activity, clinical response, and tolerability were characterized.Results: Steady-state serum eculizumab concentrations were achieved by Week 4 and were sustained throughout the 26-week treatment period. The eculizumab pharmacokinetic data were well-described by a two-compartment model with first-order elimination, including effects of body weight on pharmacokinetic parameters and plasma-exchange events on clearance. Complete inhibition of terminal complement was achieved in nearly all patients at the time of trough and peak eculizumab concentrations at all post-dose timepoints assessed (free C5 < 0.5 μg/ml in 92% of patients; in vitro hemolysis < 20% in 87% of patients). Serum eculizumab concentrations of ≥116 μg/ml achieved free C5 concentrations of < 0.5 μg/ml. Clinical efficacy and tolerability were consistent across the eculizumab exposure range.Conclusions: Rigorous, quantitative, model-based exposure–response analysis of serum eculizumab concentration and response data demonstrated that the approved eculizumab dosing (900/1,200 mg) for adults with anti-AChR antibody-positive refractory gMG rapidly achieved complete inhibition of terminal complement activation and provided sustained clinical efficacy across the eculizumab exposure range.

Disease-Modifying Effect of Japanese Cedar Pollen Sublingual Immunotherapy Tablets

Japanese cedar (JC) pollinosis is a common allergic rhinitis in Japan. JC pollen sublingual immunotherapy (SLIT) tablets are licensed for the treatment of JC pollinosis. To assess the disease-modifying effects of JC pollen SLIT tablets over 5 years (2014-2019), comprising a 3-year treatment period and 2-year follow-up. A total of 1042 patients with JC pollinosis (aged 5-64 years) were included in the study. An optimal dose-finding study was performed in the first 15 months, after which 240 patients in the placebo (P) group and 236 patients in the optimalactive dose (A) group (5000 Japanese allergy units) were re-randomized to receive P or A for an additional 18 months (designated AA, AP, PA, and PP groups). Clinical efficacy was evaluated by the total nasal symptom and medication score (TNSMS) during the peak symptom period of each JC pollen season over 3 years of treatment and 2 years of observation after treatment cessation. The AA, AP, and PA groups exhibited significantly reduced TNSMS; however, the largest relative reduction was seen in the AA group both during the treatment period (third season, 46.3% vs PP, P < .001) and during the 2-year follow-up period (fourth and fifth seasons, 45.3% and 34.0% vs PP, respectively; P < .001). The most common adverse drug reactions were mild reactions at the administration site. JC pollen SLIT tablets show sustained clinical efficacy during 3 years of treatment and sustained disease-modifying effects for at least 2 years after treatment cessation.

Focused Ultrasound Thalamotomy for the Treatment of Essential Tremor: A 2-Year Outcome Study of Chinese People.

Background: Essential tremor (ET) is a common movement disorder among elderly individuals worldwide and is occasionally associated with a high risk for mild cognitive impairment and dementia. This retrospective study aimed to determine the clinical outcome of unilateral magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy in Chinese patients with ET.Methods: In total, 31 male and 17 female patients with drug-refractory ET were enrolled in this research study from January 2017 to September 2019. The severity of tremor and disability were assessed using the Clinical Rating Scale for Tremor (CRST) within a 2-year follow-up period.Results: The mean age of the participants was 59.14 ± 13.5 years. The mean skull density ratio (SDR) was 0.5 ± 0.1. The mean highest temperature was 57.0 ± 2.4°C. The mean number of sonications was 10.0 ± 2.6. The average maximum energy was 19,710.5 ± 8,624.9 J. The total CRST scores and sub-scores after MRgFUS thalamotomy significantly reduced during each follow-up (p < 0.001). All but four (8.3%) of the patients had reversible adverse events (AEs) after the procedure.Conclusions: MRgFUS had sustained clinical efficacy 2 years after treatment for intractable ET. Only few patients presented with thalamotomy-related AEs including numbness, weakness, and ataxia for an extended period. Most Chinese patients were treated safely and effectively despite their low SDR.

Secukinumab provides sustained improvement in signs and symptoms and low radiographic progression in patients with psoriatic arthritis: 2-year (end-of-study) results from the FUTURE 5 study

ObjectiveSecukinumab provided sustained efficacy, low radiographic progression and consistent safety over 52 weeks in patients with psoriatic arthritis (PsA) in the FUTURE 5 study. Here, we report 2-year (end-of-study) results...